CN104812378A - Solid dosage form - Google Patents

Abstract

The present invention provides a solid dosage form suitable for releasing a biologically active substance in the oral cavity, wherein the dosage form comprises at least one biologically active substance and at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. Also provided is a method of producing the solid dosage form and a kit comprising the solid dosage form.

Description

solid dosage form

field of invention

The present invention relates to dosage forms suitable for administration to a subject. Preferably, the solid dosage form has a fast dissolution rate.

background

Tablets are a common dosage form used to deliver active agents to humans by oral administration. Drug delivery through the oral mucosa, such as the sublingual mucosa, allows fast-dissolving drugs to be absorbed by simple diffusion directly into the systemic circulation through the jugular vein, bypassing the gastrointestinal and hepatic first-pass effects. The sublingual route generally results in a rapid and reliable onset of action and is more suitable for fast dissolving forms.

There is an unmet need in the medical field for dosage forms with a fast dissolution rate in the oral cavity. Previous attempts to overcome the problems associated with solid dosage forms include effervescent tablets, films, chewable tablets, disintegrants and wicking agents. These dosage forms are especially suitable for patients who have difficulty swallowing, such as children and the elderly. Several techniques exist for the preparation of such dosage forms, including freeze drying, spray drying, tablet molding and tablet compression.

Freeze-drying methods have been used to prepare fast-dissolving solid dosage forms. Depending on the method of manufacture, the products obtained are characterized by a highly porous microstructure with the active agent dispersed homogeneously in the support matrix (ie mannitol, glycine, lactose, gelatin, etc.). This technology produces a product that dissolves quickly in water or in the oral cavity; however, the poor physical integrity of its physical structure severely limits further manufacturing operations, such as forming blister packs. Furthermore, freeze-drying techniques have high production costs in the manufacture of such dosage forms due to the lengthy duration of each freeze-drying cycle (typically 24 to 48 hours). The complexity of industrial plants is another important factor against the large-scale use of this technology for the development of fast-dissolving tablets. Furthermore, thermal shock as a direct consequence of each freeze-drying cycle may physically alter the physicochemical properties of the outer membrane of the microencapsulated particles.

In the freeze-drying process, gelatin and other gelatin-related materials have been used to formulate pharmaceuticals in a fast-dissolving form. Gelatin is a carrier or structure former and it is commonly used in the preparation of fast-dissolving forms of a wide range of pharmaceuticals. Gelatin provides strength to the dosage form, thus preventing the dosage form from cracking and disintegrating. This is especially a problem when the dosage form is removed from the blister pack. Gelatin is advantageous in terms of rapid drug dissolution from the dosage form because it provides rapid dissolution of the dosage form once it is placed in the oral cavity.

Gelatin is a protein obtained by partially hydrolyzing animal collagenous tissues such as skin, tendons, ligaments and bones. However, a significant problem with mammalian-derived gelatin is that it has a bland taste. This results in instant formulations requiring the use of sweeteners and flavoring agents to mask and mask the taste of the gelatin component. Another problem with conventional mammalian-derived gelatin is that it requires the use of heat to affect gelatin dissolution. This extra step adds time and cost to the manufacturing process.

Another problem with using gelatin-based materials as fast-dissolving bases is that gelatin can increase the viscosity of the solution over time. This can lead to processing difficulties. Furthermore, gelatin can cause homogeneity and settling problems associated with gelatin solutions during holding. Other disadvantages of gelatin formulations include susceptibility to bacterial growth, and the fact that it comes from animal sources is disliked by some individuals.

Other agents that have been used to replace gelatin in fast dissolving forms are starches and modified starches. One problem with starch is that it has a grainy feel to the patient in the mouth and can lead to patient dissatisfaction. Many modified starches can also cause this problem. Also, they are expensive.

Ketamine is a rapid-acting general anesthetic approved for intravenous injection only. In recent years, interest in its use as an adjunct in acute and chronic pain management at non-narcotic doses has increased. Its pain-modifying properties are due to its antagonism of N-methyl-D-aspartate (NMDA) receptors by non-competitive binding to the phencyclidine binding site. Ketamine potently produces analgesia when administered at sub-anesthetic levels and also exhibits opioid-sparing activity, but the mechanisms behind this remain poorly understood. Ketamine's analgesic efficacy is well correlated with its inhibitory effect on N-methyl-D-aspartate receptor-mediated pain facilitation and decreased activity of brain structures that respond to noxious stimuli. Therefore, its utility in the management of acute pain is of interest. Although parenteral administration of ketamine may provide almost immediate pain relief, this route may not be suitable or convenient for the patient.

Cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitors are a class of compounds that reduce the level of cGMP degradation in smooth muscle, leading to smooth muscle relaxation and increased blood flow. The best known inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) is sildenafil, specifically sildenafil citrate or Sildenafil is usually taken in tablet form about 30 minutes to 4 hours before sexual intercourse. However, faster onset delivery of sildenafil or other cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitors may be advantageous, especially in their other uses as therapeutics for pulmonary hypertension hour.

Epinephrine is a hormone and neurotransmitter used in the treatment of a number of conditions, including: cardiac arrest and other cardiac rhythm disorders resulting in reduced or absent stroke volume; allergies; superficial bleeding; and asthma, bronchial Cramps and croup. Epinephrine is often delivered via an autoinjector delivery system; however, an alternative delivery system for rapid delivery may be beneficial for those who cannot safely administer an autoinjector (such as children and caregivers of children who are not familiar with autoinjector devices) and who do not wish to use the autoinjector. installer.

Therefore, the delivery of biologically active substances to patients by oral administration, such as N-methyl-D-aspartate receptor antagonists, epinephrine or cyclic guanosine monophosphate (cGMP) type 5 phosphate, is therefore not an issue in the art. A need exists for fast dissolving forms of diesterase (PDE5) inhibitors, wherein the dosage form dissolves rapidly in the mouth of the patient, and wherein the dosage form does not use large amounts of mammalian gelatin.

Summary of the invention

According to one aspect of the present invention, there is provided a solid dosage form suitable for releasing a biologically active substance in the oral cavity, wherein the dosage form comprises:

(a) at least one biologically active substance, and

(b) at least one matrix-forming agent, wherein the dosage form substantially dissolves in the oral cavity.

Preferably, the solid dosage form is a fast dissolving solid dosage form.

Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is adrenaline (epinephrine) or an adrenaline salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Preferably, the dosage form is adapted to leave no detectable residues of the dosage form in the oral cavity by the patient.

Preferably, the dosage form disintegrates rapidly in the oral cavity and allows the fast-dissolving bioactive substance to be absorbed by diffusion through the oral mucosa and directly into the systemic blood circulation. In this way, the hepatic first-pass effect is avoided. Preferably, the dosage form is suitable for delivery via the jugular vein directly into the systemic circulation, thereby bypassing the gastrointestinal and hepatic first-pass effects.

According to another aspect of the present invention, there is provided a method for producing a solid dosage form of the present invention, comprising the steps of:

(a) combining at least one matrix-forming agent with a biologically active substance to form a homogeneous mixture; and

(b) freeze-drying the mixture to prepare the solid dosage form of the present invention.

Preferably, the method is a method for producing a fast dissolving solid dosage form.

Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

According to another aspect of the present invention, there is provided a kit comprising:

(a) a solid dosage form, wherein the dosage form comprises:

(i) at least one biologically active substance, and

(ii) at least one matrix forming agent, and

(b) its instruction manual

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

According to another aspect of the present invention there is provided a solid dosage form suitable for releasing at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the oral cavity, wherein said dosage form comprises:

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor; and

(b) at least one matrix forming agent;

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

According to another aspect of the present invention there is provided a solid dosage form suitable for releasing in the oral cavity an active substance that binds to one or more adrenergic receptors, wherein said dosage form comprises:

(a) active substances that bind to one or more adrenergic receptors; and

(b) at least one matrix forming agent;

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt.

According to another aspect of the present invention, there is provided a solid dosage form suitable for releasing an N-methyl-D-aspartate receptor antagonist in the oral cavity, wherein said dosage form comprises:

(a) N-methyl-D-aspartate receptor antagonists; and

(b) at least one matrix forming agent;

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

According to another aspect of the present invention there is provided a wafer comprising a solid dosage form adapted to release a biologically active substance in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate. The wafer may be accompanied by instructions for its use.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the solid dosage form of the present invention. Preferably, the solid dosage form is a fast dissolving solid dosage form.

Disclosure of Invention

solid dosage form

According to one aspect of the present invention, there is provided a solid dosage form suitable for releasing a biologically active substance in the oral cavity, wherein the dosage form comprises:

(a) at least one biologically active substance, and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity.

Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists.

Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. If the antagonist is ketamine, then the ketamine is preferably a ketamine salt, such as ketamine hydrochloride. In one embodiment, ketamine is in the form of a racemic mixture of the R and S enantiomers. Preferably, ketamine is a mixture of two enantiomers R-(-) and S-(+).

Preferably, the biologically active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt.

Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

In one embodiment, the biologically active substance is present in an amount, by dry weight of the solid dosage form, selected from the group consisting of: 0.01 to 95% by weight; 0.1 to 75% by weight and 1 to 45% by weight.

Preferably, the dosage form disintegrates rapidly in the oral cavity and allows the fast-dissolving bioactive substance to be absorbed by diffusion through the oral mucosa and directly into the systemic blood circulation. In this way, the hepatic first-pass effect is avoided. Preferably, the dosage form is suitable for delivery via the jugular vein directly into the systemic circulation, thereby bypassing the gastrointestinal and hepatic first-pass effects.

By "fast dissolving", it preferably means that once placed in the oral cavity, the dosage form substantially dissolves within a time period selected from the group consisting of: less than 2 minutes after application of the dosage form; less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3 seconds; and less than 2 seconds. Preferably, the dissolution rate of the fast dissolving form is higher than that of the conventional dosage form.

More preferably, once placed in the oral cavity, the "instantly dissolving" solid dosage form completely dissolves within a time period selected from the group consisting of: less than 2 minutes after administration of the dosage form; less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3 seconds; and less than 2 seconds.

By "substantially" it is meant that at least 60% of the fast dissolving form has dissolved in the oral cavity within the selected time period. Preferably, at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97% or 98% of the fast dissolving form has dissolved in the oral cavity within the selected time period. Most preferably, at least 99% of the fast dissolving form has dissolved in the oral cavity within the selected time period.

In a highly preferred embodiment of the invention, there are no patient-detectable residual residues of the dosage form according to the invention after administration. Preferably, the dosage form dissolves completely after oral, preferably sublingual, administration to a patient. Therefore, the subject did not have an urgency to swallow the dosage form. In particular, pharmaceutical compositions may, for example, be designed for buccal or sublingual delivery.

· Active agent

Biologically active substances include active compounds and compounds intended for veterinary and human use such as, but not limited to: pharmaceutical actives, nutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural products, foods, vitamins, nutrients, biologics , amino acids, proteins, peptides, nucleotides and nucleic acids. In a preferred form, the biologically active substance is suitable for oral administration.

In a preferred embodiment of the invention, the biologically active substance is an organic compound. In a highly preferred embodiment of the invention, the biologically active substance is an organic, therapeutically active compound for human use. In another embodiment of the invention, the biologically active substance is an inorganic compound. When the biologically active substance is a drug, it can be of neutral species, basic or acidic, and acid or base salts. The present invention is not limited to any particular class, application type, chemical type or functional grouping of drugs.

Biologically active substances are generally agents of skill in the art for which rapid dissolution improvements for oral administration are desired. Biologically active substances can be conventional active agents or drugs.

Examples of biologically active substances suitable for use in the present invention include actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and their analogs, homologues and primary derivatives. Bioactive substances may be selected from various known classes of drugs including, but not limited to: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, antifungal agents, oncology therapies, Antiemetics, analgesics, cardiovascular agents, anti-inflammatory agents (such as NSAIDs and COX-2 inhibitors), anthelmintics, antiarrhythmics, antibiotics (including penicillin), anticoagulants, antidepressants, antidiabetics antiepileptic, antihistamine, antihypertensive, antimuscarinic, antimycobacterial, antineoplastic, immunosuppressant, antithyroid, antiviral, anxiolytic Sedatives, Sedatives (Hypnotics and Tranquilizers), Astringents, Alpha-Adrenergic Receptor Blockers, Beta-Adrenergic Receptor Blockers, Blood Products and Substitutes, Cardiac Inotropes, Contrast Media, Cough Inhibitors (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergic agents (anti-Parkinson's disease agents), hemostatic agents, immunological agents, lipid-modulating agents, muscle relaxants, pseudo- Parasympathetic agents, parathyroid calcitonin and bisphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including steroids), antiallergic agents, stimulants and anorectics, sympathomimetics, thyroid agents , vasodilators and xanthines.

A description of these classes of biologically active substances and a list of substances within each class can be found in 'The Extra Pharmacopoeia', 31st Edition (The Pharmaceutical Press, London, 1996) and in 'Physician's Desk Reference' (60th Edition, 2005) , all of which are expressly incorporated herein by reference and are familiar to those skilled in the art. Active agents are commercially available and/or can be prepared by techniques known in the art.

Additionally, examples of suitable biologically active substances include, but are not limited to, those of the following:

Analgesics and anti-inflammatory agents: aloxiprin, auranofm, azapropazone, benorylate, diflunisal, etodolac (etodolac), fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone, phenylbutazone Azone (phenylbutazone), piroxicam (piroxicam), sulindac (sulindac).

Insect repellants : albendazole, bepheniumhydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole ), oxamniquine, oxfendazole, oxantelembonate, praziquantel, pyrantel embonate, thiabendazole (thiabendazole).

Antiarrhythmic agents : amiodarone HCl, disopyramide, flecainide acetate, quinidine sulphate.

Antibacterial agents : benethamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin ( cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid , nitrofurantoin, rifampicin, spiramycin, sulphabenzamide, sulphadoxine, sulphamethazine, sulphacetamide , sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim.

• Anticoagulants: dicoumarol, dipyridamole, nicoumalone, phenindione.

Antidepressants: amoxapine, ciclazindol, maprotiline HCl, mianserin HCl, nortriptyline HCl , trazodone HCl, trimipramine maleate.

Antidiabetic agents: acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tola Sulphonylurea (tolazamide), tolbutamide (tolbutamide).

Antiepileptics : beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methyl Methylphenobarbitone, oxcarbazepine, paramethadione, phenacemide, phenobarbitone, phenytoin, phensuximide, Primidone, sulthiame, valproic acid.

Antifungal agents : amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, Griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate ( sulconazole nitrate), terbinafine HCl, terconazole, tioconazole, undecenoic acid.

• Antigout agents : allopurinol, probenecid, sulphinpyrazone.

Antihypertensive agents : amlodipine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanidine acetate Guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine ), phenoxybenzamine HCl, prazosin HCl, reserpine, and terazosin HCl.

Antimalarial agents : amodiaquine, chloroquine, chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil hydrochloride HCl), pyrimethamine, quinine sulfate.

Anti-migraine agents: dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, phenylthiazine maleate ( pizotifen maleate), sumatriptan succinate.

Antimuscarinic agents : atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscine butyl bromide, hyoscine (hyoscyamine), mepenzolate bromide, orphenadrine, oxyphencylcimine HCl, and tropicamide.

Antineoplastic agents and immunosuppressants : aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporine (cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate, testis Esters (testolactone).

Antiprotozoal agents : benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furoate, di dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.

Antithyroid agents : carbimazole, propylthiouracil.

Anxiolytics , sedatives, hypnotics, and tranquilizers: alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam , bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlormethiazole, chlorpromazine ), clobazam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, fluanisone ), flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol Alcohol (haloperidol), lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitroazepam (nitrazepam), oxazepam, pentobarbitone, perphenazine, pimozide, prochlorperazine, sulpiride , temazepam, thioridazine, triazolam, zopiclone.

Beta-blockers : acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol nadolol, oxprenolol, pindolol, propranolol.

Cardiac inotropes : amrinone, digitoxin, digoxin, enoximone, lanatoside C, methyl digoxin ( medigoxin).

Corticosteroids : beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fluoride acetate Fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone prednisolone, prednisone, triamcinolone.

Diuretics : acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, diuretic ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.

• Anti-Parkinson agents: bromocriptine mesylate, lysuride maleate.

Gastrointestinal agents : bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotinib Famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCl, ranitidine hydrochloride Butyl (ranitidine HCl), sulfasalazine (sulphasalazine).

Histamine H1-receptor antagonists : acrivastine, astemizole, cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate, flunarizine HCl, loratadine, meclozine HCl, oxatomide, terfenadine, koji Triprolidine.

- Lipid regulators : bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

• Local anesthetic: neuro-muscular agent: pyridostigmine.

Nitrates and other anticolic agents: amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.

Nutrients : beta carotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K.

Opioid analgesics : codeine, dextropropoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine base (morphine), nalbuphine, pentazocine, midazolam, fentanyl.

Oral vaccines: Vaccines designed to prevent or alleviate the symptoms of diseases of which the following is a representative, non-exclusive list: Influenza, Tuberculosis, Meningitis, Hepatitis, Pertussis, Polio, Tetanus , diphtheria, malaria, cholera, herpes, typhoid, HIV, AIDS, measles, Lyme disease, traveler's diarrhea, hepatitis A, B, and C, otitis media, dengue fever, rabies, para Influenza, Rubella, Yellow Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q Fever, Haemorrhegic Fever, Argentine Hemorrhagic Fever, Bone Ulcers, Chagas Disease, Urinary tract infections, pneumococcal disease, mumps, and Chikungunya caused by E. coli.

Vaccines to prevent or alleviate symptoms of other disease syndromes, of which the following is a representative, non-exclusive list of causative organisms: Vibrio species, Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis gondii, Cytomegalovirus, Chlamydia species, Streptococcus species (Streptococcal species), Norwalk Virus, Escherischia coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhae, Meningitis Neisseria meningiditis, Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex, Clostridium Clostridia species, Respiratory Syncytial Virus, Klebsielia species, Shigella species, Pseudomonasaeruginosa , Parvovirus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ross River Virus, JC Virus, Rhodococcus equi, Moraxella catarrhalis, Borreliaburgdorferi, and Pasteurella haemolytica ). Other specific examples include opioids such as fentanyl or midazolam.

• Vaccines against non-infectious immune-modulated disease states: such as surface and systemic allergic conditions such as Hayfever, asthma, rheumatoid arthritis and carcinoma.

· Vaccines for veterinary use: including those against: Coccidiosis, Newcastle Disease, Enzooticpneumonia, Feline leukemia, Atrophicrhinitis ), Erysipelas, Foot and Mouth disease, Swine, pneumonia and other disease conditions affecting companion and farm animals and other infectious and autoimmune disease conditions.

Proteins, peptides and recombinant drugs : insulin (hexameric/dimeric/monomeric), glucagon, growth hormone (somatostimulator), polypeptide or their derivatives (preferably molecular weight 1000 to 300,000), Calcitonin and its synthetically modified forms, enkephalins, interferons (especially alpha-2 interferon for the common cold), LHRH and analogs (nafarelin, Serelin (buserelin), Zolidex), GHRH (growth hormone releasing hormone), secretin, bradykinin antagonists, GRF (growth releasing factor), THF, TRH (thyrotropin releasing hormone), ACTH analogs, IGF (insulin-like growth factor), CGRP (calcitonin gene-related peptide), atrial natriuretic peptide, vasopressin and analogs (DDAVP, lysine vasopressin), factor VIII, G - CSF (granulocyte colony stimulating factor), EPO (erythropoietin).

Sex hormones: clomiphene citrate, danazol, ethinyloestradiol, medroxyprogesterone acetate, mestranol, methyltestosterone , norethisterone, norgestrel, oestradiol, conjugated estrogen, progesterone, stanozolol, stiboestrol, testosterone (testosterone), tibolone (tibolone).

Spermicide : nonoxynol 9.

Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol, perine Merlin (pemoline).

Notwithstanding the general applicability of the methods of the present invention, more specific examples of biologically active substances include, but are not limited to: haloperidol (dopamine antagonist), DL isoproterenol hydrochloride (beta-adrenergic agonist), special Terfenadine (H1 antagonist), propranolol hydrochloride (beta-adrenergic antagonist), desipraminehydrochloride (antidepressant), sildenafil citrate, tadalafil (tadalafil) and vardenafil (vardenafil). Adjunct analgesics (cyclooxygenase inhibitors), fenamic acid, piroxicam, Cox-2 inhibitors, naproxen, and other analgesics may benefit from formulation into the oral dosage forms of the present invention.

Other examples of biologically active substances include, but are not limited to: alfaxalone, acetyl digoxin, acyclovir analogs, alprostadil, aminofostin, anipamil, antithrombin III, atenolol, azidothymidine, beclobrate, beclomethasone, belomycin , benzocaine (benzocaine) and derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate (bezafibrate), binovum (binovum), biperiden (biperiden), bromide Bromazepam, bromocryptine, bucindolol, bufIomedil, bupivacaine, busulfan, cadralazine , camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin, cefalotin, Cefamandole, cefazedone, cefluoroxime, cefinenoxime, cefoperazone, cefotaxime, cefoxitin, cefoxime cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid, ciclonicate, ciglitazone, clonidine , cortexolone, corticosterone, cortisol, cortisone, cyclophosphamide, cyclosporine A and other cyclosporines, arabinosporine Cytarabine, desocryptin, desogestrel, dexamethasone ester (such as dexamethasone acetate), dezocine ine), diazepam, diclofenac, dideoxyadenosine, dideoxyinosine, digitoxin, digoxin, dihydroergotamine, dihydroergotoxin, diltiazem ( diltiazem), dopamine antagonists, doxorubicin, econazole, endralazine, enkephalins, enalapril, epoprostenol, estradiol alcohol, estramustine, etofibrate, etoposide, factor ix, factor viiii, felbamate, fenbendazole, fenofibrate, Fexofenedine, flunarizin, flurbiprofen, 5-fluorouracil, flurazepam, fosfomycin, fosfomycin Fosmidomycin, furosemide, gallopamil, gamma interferon, gentamicin, gepefrine, gliclazide, glipizide ( glipizide, griseofulvin, haptoglobulin, hepatitis B vaccine, hydralazine, hydrochlorothiazide, hydrocorticosterone, ibuprofen, ibuproxen ( ibuproxam), indinavir, indomethacin, iodinated aromatic X-ray contrast agent (such as iodacic acid), ipratropium bromide, ketoconazole ), ketoprofen, ketotifen, ketotifen fumarate, K-strophanthin, labetalol, Lactobacillus vaccine, lidocaine, lidoflazin, lisuride, lisuridehydrogen maleate, lorazepam, lova Statin (lovastatin ), mefenamic acid, melphalan, memantin, mesulergine, metergoline, methotrexate, methyl digoxin ( methyldigoxin), methylprednisolone, metronidazole, metisoprenol, metipranolol, metkephamide, metolazone , metoprolol, metoprolol tartrate, miconazole, miconazole nitrate, minoxidil, misonidazole , molsidomin, nadolol, nafiverine, nafazatrom, naproxen, natural insulin, nesapidil, Nicardipine, nicorandil, nifedipine, niludipine, nimodipine, nitrazepam, nitrendipine, nitrocamptothecin ( nitrocamptothesin), 9-nitrocamptothesin, olanzapine, oxazepam, oxprenolol, oxytetracycline, penicillins (such as benzamine Penicillin G, Penicillin O), phenylbutazone, picotamide, pindolol, piposulfan, piretanide, piribedil ( piribedil), piroxicam, pirprofen, plasminogen activator, prednisolone, prednisone, pregnenolone, procarbazine, procarbazine Procaterol, progesterone, proinsulin, propafenone, propanolol, propofyllin, propofol, propofol Navolol, raloxifene, rifapentin, simvastatin, semisynthetic insulin, sobrerol, somastotine and its derivatives Drugs, growth-stimulating hormone, stilamine, sulfinalol hydrochloride, sulfinpyrazone, suloctidil, suprofen, sulprostone, Synthetic insulin, talinolol, taxol, taxotere, testosterone, testosterone propionate, testosterone undecanoate, tetracaine HI, tiaramide hydrochloride HCl), tolmetin, tranilast, triquilar, tromantadine HCl, urokinase, valium, verapamil ( verapamil), vidarabine, vidarabine phosphate sodium salt, vinblastine, vinburin, vincamine, vincristine, vinaigrette Vindesine, vinpocetine, vitamin A, vitamin E succinate, and X-ray contrast agents.

Furthermore, it is also expected that novel chemical entities (NCEs) and other actives suitable for delivery by the solid dosage forms of the present invention will be created or become commercially available in the future and be useful as biologically active substances.

A biologically active substance may be an active substance that binds to one or more adrenergic receptors. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine (adrenaline hormone) or a salt of epinephrine, such as epinephrine bitartrate or epinephrine hydrochloride. Alternatively, active substances that bind to one or more adrenergic receptors may be provided in the form of adrenaline-related analogs and compounds such as norepinephrine, isoproterenol, or sympathomimetic agents such as Tyramine, ephedrine, pseudoephedrine, amphetamine, salbutamol, and terbutaline.

The biologically active substance may be an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

The biologically active substance may be a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Preferably, the solid dosage form is in a form selected from the group consisting of wafers; tablets; capsules; pills; powders; The solid dosage form should be suitable not to leave a detectable residue of the dosage form in the oral cavity by the patient. Regardless of the form in which the solid dosage form is provided; it should disintegrate rapidly in the oral cavity and allow the fast-dissolving bioactive substance to be absorbed by diffusion through the oral mucosa and directly into the systemic blood circulation. Preferably, the solid dosage form is a fast dissolving solid dosage form.

·Components

Preferably, the solid dosage form is substantially free of starch. In another embodiment of the invention, the pharmaceutical composition comprising the solid dosage form is also substantially free of starch. Preferably, the solid dosage form is a fast dissolving solid dosage form.

The precise amount of biologically active material in a solid dosage form will depend on the type of biologically active material selected. However, the active substance will generally be present in an amount of 0.02 to 95%, preferably 0.02 to 20% or preferably 0.1 to 75%, 1 to 45%, by dry weight of the dosage form.

The biologically active substance may generally be present in the solid dosage form in an amount selected from the group consisting of: 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg;

Preferably, the solid dosage form of the invention also comprises at least one matrix forming agent.

In prior art freeze-drying systems, gelatin is most commonly used as a carrier or structure-forming agent due to its wall-forming ability. Gelatin is a water soluble polymer, and therefore, when mixed with an active pharmaceutical ingredient in water; the viscosity of the solution increases over time which can lead to a decrease in the solubility of poorly soluble drugs in the mixture and create a mixture of drugs in the gelatin matrix. Suspension. This can cause phase separation to occur; and drugs in amorphous or crystalline form may not be homogeneously dispersed in the matrix, which will ultimately affect dissolution and absorption of the final product. Accordingly, gelatin is preferably absent from the solid dosage forms of the invention.

The effectiveness of the solid dosage forms of the present invention relies on the dissolution of the bioactive substance in a small volume of fluid, such as in the oral cavity, prior to absorption into the systemic circulation. Therefore, the dissolution rate of the dosage form is important. In a preferred embodiment of the invention, the solid dosage form comprises a superdisintegrant as at least one matrix-forming substance.

Other polymeric materials suitable for forming the matrix in the solid dosage form can be selected for a particular application, especially for a site-specific drug delivery system (eg, in the oral cavity). The matrix forming agent of the present invention may be selected from the group consisting of: non-mammalian gelatin, dextrin, soybean protein, wheat protein, psyllium seed protein, acacia gum, guar gum, agar gum, xanthan gum, polysaccharides; seaweed salt; sodium carboxymethylcellulose; carrageenan; dextran; pectin; sugar; amino acid; starch; modified starch; carboxymethylcellulose; hydroxypropylmethylcellulose; hydroxypropylcellulose and Methylcellulose inorganic salt; synthetic polymer; pullulan, polypeptide/protein or polysaccharide complex.

The matrix-forming substance in solid dosage forms can be a carbohydrate. Preferably, the carbohydrate is selected from the group consisting of: mannitol; dextrose; lactose; galactose; trehalose;

In a highly preferred embodiment, at least one matrix forming agent in the solid dosage form is glycine. Glycine is an amino acid with excellent wetting properties and is suitable for fast-dissolving formulations. Low levels of glycine can be used in the formulations of the invention to control the dissolution rate of the dosage form. In addition, glycine can also be used as an anti-slump agent to maintain dosage forms from shrinkage during the manufacturing process or after packaging. In one embodiment, glycine is present in the dosage form of the invention in an amount of from 0.2 to 7.5%, more preferably from about 0.5% to about 5%, by dry weight of the dosage form. Preferably, glycine is present in an amount of 0.5 to 5% by weight, based on the dry weight of the composition of the dosage form.

In a highly preferred embodiment, at least one matrix-forming agent in the solid dosage form is sodium carboxymethylcellulose. When the at least one matrix forming agent is sodium carboxymethylcellulose, the polymer is present at a concentration of from about 0.1% to about 19% by dry weight of the solid dosage form. In a preferred embodiment, sodium carboxymethylcellulose is present in an amount of from about 0.1% to about 15% by dry weight of the dosage form. In a highly preferred embodiment of the invention, sodium carboxymethylcellulose is present in an amount of from about 0.1% to about 1.0% by dry weight of the solid dosage form. Preferably, sodium carboxymethylcellulose is present in an amount selected from the group consisting of: 0.05% to 19%; 0.1% to 15%; and 0.1% to 10%, by dry weight of the composition of the dosage form.

In a further embodiment of the invention, the dosage form comprises pullulan as at least one matrix-forming agent. Amylopectin can increase the release of bioactive agents by facilitating the disintegration of the formulation. Pullulan may be present in the dosage form at a concentration of about 2% up to no greater than 20% by dry weight of the solid dosage form. Amylopectin may be present in an amount from about 2% to about 17% by dry weight of the dosage form. Preferably, amylopectin is present in an amount selected from the group consisting of: 2% to 17%; and 2% to 15%, by dry weight of the composition of the dosage form.

According to another embodiment of the invention, the solid dosage form may comprise a matrix forming agent, such as mannitol. Mannitol is an ingredient that can contribute to the crystal structure and impart hardness to the dosage form. When mannitol is present in the dosage form, it is present at a concentration of from about 5% to about 80%, preferably from about 10% to about 60%, and most preferably from about 10% to about 50% by dry weight of the dosage form.

Solid dosage forms may contain inorganic salts. Preferably, the inorganic salt is selected from the group consisting of: sodium phosphate; sodium chloride; and aluminum silicate.

The solid dosage forms of the present invention may contain amino acids. Preferably, the amino acid is selected from the group consisting of: glycine; L-alanine; L-aspartic acid; L-glutamic acid; L-hydroxyproline; L-isoleucine; L-leucine acid; and L-phenylalanine.

Solid dosage forms of the invention may also preferably be substantially free of starch.

To achieve rapid dissolution of the biologically active substance from the solid dosage form of the invention, a diluent may be added as at least one matrix-forming substance. Diluents include microcrystalline cellulose (such as AvicelPH and Avicel PH ), lactose, starch and sorbitol. These diluents may be present in the dosage form alone or in mixtures in varying ratios, and may range from about 1% to about 80%, preferably from about 2% to about 50%, individually or cumulatively.

In one embodiment of the invention, the solid dosage form comprises microcrystalline cellulose as at least one matrix forming agent. Microcrystalline cellulose can act as a filler and a binder in the dosage forms of the invention. Microcrystalline cellulose can be compacted with minimal compression pressure and yields a firm, stable dosage form, preferably a fast dissolving form. Due to its large surface area and high internal porosity, microcrystalline cellulose is capable of absorbing and retaining large amounts of water, which is desirable in the dosage forms of the present invention. When the solid dosage forms of the present invention comprise microcrystalline cellulose, it is present in an amount of from about 1% to about 10%, and preferably from about 1% to about 8%, by dry weight of the dosage form.

The solid dosage form or pharmaceutical composition of the invention may preferably be substantially free of Avicel.

In another preferred embodiment, the solid dosage form comprises at least one lubricant. Dosage forms of the invention may include lubricants such as polyethylene glycol (PEG) 1000, 2000, 4000 and 6000, sodium lauryl sulfate, fats or oils. One advantage of using these lubricants is to aid in the removal of the dosage form from the mold. These lubricants may be present in the dosage form alone or in mixtures in different ratios and may be between 0.05% and 5%, preferably between 0.1% and 2%, preferably about 1.5%, individually or cumulatively. In one embodiment, the composition comprises between 0.05% and 5% polyethylene glycol 2000, preferably between 0.1% and 2% polyethylene glycol 2000, preferably about 1.5% polyethylene glycol 2000, by dry weight of the dosage form Polyethylene glycol 2000 or a mixture of various glycols. Alternatively, PEG 2000 can be replaced by PEG 1000.

In another preferred embodiment, the solid dosage form comprises at least one buffering agent. Preferably, the buffering agent in the solid dosage form provides a saliva pH of 7.0 to 7.8 when dissolved in the oral cavity. Such buffering agents can improve sublingual absorption of weak base compounds. The solid buffering agent may be selected from the group comprising sodium monobasic phosphate dehydrate, sodium hydrogen phosphate disodium, sodium bicarbonate and sodium carbonate, either alone or in admixture in varying ratios at about 0.01% by weight of the composition Up to about 10% concentration is present in the dosage form.

Alternatively, the solid buffering agent may be selected from a list comprising alginic acid, ascorbic acid, citric acid, malic acid, succinic acid and tartaric acid, alone or in mixtures in varying ratios at about 0.01 by weight of the composition. % to about 10% is present in the dosage form. Preferably, the buffering agent is citric acid, which may be present at a concentration of about 0.01% to about 10%, more preferably between 0.1% and 5%, most preferably about 2.0%, by weight of the solid dosage form.

For example, if the biologically active substance in the solid dosage form is sildenafil, then the molecular structure of sildenafil has both a weakly acid center and a weakly basic center. This means that the solubility of sildenafil in water is affected by the pH of the solution, and the two optimum pH (pHmax) values are 4.5 and 10.24. Thus, to improve transmucosal absorption of sildenafil, solid dosage forms may contain solid buffering agents that produce a salivary pH of 5.0 to 6.0 when dissolved in the oral cavity. Increasing the pH of the sildenafil solution reduces the ratio of unionized particles to ionized particles, which leads to enhanced transmucosal absorption.

Preferably, the buffering agent is sodium carbonate, which may be present at a concentration of about 0.01% to about 10%, more preferably between 0.1% and 1%, most preferably about 0.3% or 0.5% by weight of the solid dosage form exist.

In certain embodiments, solid dosage forms can include at least one absorption enhancer. Absorption enhancers can be polysaccharides, and can be positively charged. Preferably, the absorption enhancer is beta-cyclodextrin or its derivatives. The beta-cyclodextrin or derivative may be present at a concentration of about 0.01% to about 10%, preferably between 0.2% and 2%, and most preferably about 1% by dry weight of the dosage form. Alternatively, the at least one absorption enhancer may comprise glyceryl trinitrate (also known as GTN or nitroglycerin) or a derivative thereof. Glyceryl trinitrate or derivatives may be present at a concentration of from about 0.01% to about 20%, more preferably between 0.2% to 4%, and most preferably about 2%, by dry weight of the dosage form.

The solid dosage forms of the present invention may contain flocculants to maintain uniform distribution of the biologically active substance in the matrix during the manufacturing process. The flocculant can be glue. The gum is preferably xanthan gum. Xanthan gum may be present at a concentration of about 0.01% to about 10%, preferably about 0.2% to 2%, and most preferably about 1% by dry weight of the solid dosage form.

In another preferred embodiment, the solid dosage form comprises at least one surfactant. To aid in the dissolution of biologically active substances into aqueous environments such as the oral cavity, surfactants can be added to the solution as wetting agents. Suitable surfactants include anionic detergents such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate and sodium dioctyl sulfonate. Cationic detergents can be used and include benzalkonium chloride or benzethonium chloride. The list of possible non-ionic detergents includes lauromacrogol 400, polyoxyethylene 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glyceryl monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. These surfactants may be present in the dosage form alone or in mixtures in varying ratios. Preferably, surfactants aid in producing fast-dissolving solid dosage forms.

Additives that potentially enhance the uptake of the biologically active substance may also be present in the solid dosage form. Said additives may be selected from the list comprising fatty acids such as oleic acid, linoleic acid and linoleic acid.

To enhance the aesthetic and taste appeal of a solid dosage form to a subject, the dosage form may also contain at least one additive such as a coloring or flavoring agent. Coloring agents may preferably be FD&C Dye No. 2 Blue and Red No. 40; flavoring agents may be selected from the list comprising: orange, mint, raspberry and caramel, and/or sweeteners such as aspartame and saccharin, or a mixture of two or more flavorings.

Accordingly, in a highly preferred embodiment, the present invention provides a solid dosage form adapted to release a biologically active substance in the oral cavity, wherein said dosage form comprises:

(a) at least one biologically active substance, and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity; wherein the dosage form comprises 0.29% sodium carbonate, 0.59% sodium carboxymethylcellulose, 1.48% PEG 2000, 2.97% glycine, 5.93% microcrystalline cellulose; 14.84% branched Starch, 29.67% lactose, and 44.23% mannitol as a dry weight of the solid dosage form; and which did not result in substantially detectable levels of residue left in the patient's mouth. Preferably, the solid dosage form is a fast dissolving solid dosage form. PEG 2000 can be replaced by PEG 1000 with the same advantages as the oral dosage forms above.

Preferably, the biologically active substance in the solid dosage form of the present invention is selected from the list comprising at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, combined with one or more Active substance for adrenergic receptors, and N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

· Carriers and excipients

As discussed above, solid dosage forms of the present invention may include one or more pharmaceutically acceptable carriers. The use of such pharmaceutically acceptable carriers for the manufacture of medicaments as solid dosage forms, including fast-dissolving solid dosage forms, is well known in the art. Unless any conventional pharmaceutically acceptable carrier is incompatible with the biologically active material, it is contemplated for use in the manufacture of the solid dosage forms of the invention.

The pharmaceutically acceptable carrier of the present invention may include one or more of the following examples:

(1) Surfactants and polymers, including but not limited to polyethylene glycol (PEG), polyvinylpyrrolidone, polyvinyl alcohol, crospovidone, polyvinylpyrrolidone-polyvinyl acrylate copolymer, cellulose derived substances, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, Polyols and their polymers, emulsifiers, sugar gums, starches, organic acids and their salts, vinylpyrrolidone and vinyl acetate; and/or

(2) Binders, such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and/or

(3) fillers such as lactose monohydrate, anhydrous lactose, mannitol, microcrystalline cellulose, and various starches; and/or

(4) lubricants, such as agents acting on the fluidity of the powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; and/or

(5) Sweeteners, such as any natural or artificial sweetener, including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and accsulfame K; and/or

(6) flavoring agents; and/or

(7) Preservatives, such as potassium sorbate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid and its salts, other esters of p-hydroxybenzoic acid (such as butyl p-hydroxybenzoate), alcohol (such as ethanol or benzyl alcohol), phenolic chemicals (such as phenol), or quaternary compounds (such as benzalkonium chloride); antioxidants such as ascorbic acid, potassium sorbate, sodium bisulfate, sodium metabisulfite, and sorbic acid; and / or

(8) buffering agent; and/or

(9) Diluents, such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugar and/or mixtures of any of the foregoing; and/or

(10) Wetting agents such as corn starch, potato starch, corn starch and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate and mixtures thereof; and/or

(11) disintegrants; and/or

(12) Effervescent agents, such as effervescent counterparts, such as organic acids (such as citric, tartaric, malic, fumaric, adipic, succinic and alginic acids and anhydrides and acid salts), or Carbonates (such as sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate) or bicarbonates (such as sodium or potassium bicarbonate);

(13) Absorption enhancers, such as glyceryl trinitrate; and/or

(14) Other pharmaceutically acceptable excipients.

In another embodiment, more than one biologically active substance may be incorporated into the solid dosage forms of the present invention. In one example, if the biologically active substance is epinephrine, then a fast-dissolving solid dosage form can be achieved that provides different release profiles - early release from epinephrine and later release from larger average size epinephrine.

Solid dosage forms of the invention suitable for use in animals, and in particular humans, typically must be sterile and stable under the conditions of manufacture and storage. Solid dosage forms of the invention comprising biologically active substances may be formulated as solids, liposomes, or other ordered structures suitable for high drug concentrations suitable for oral delivery.

The actual dosage strength of the biologically active material in the solid dosage forms of the invention will vary depending on the nature of the biologically active material and the potential increased efficacy attributable to the advantages of providing and administering the biologically active material. Thus, as used herein, a "therapeutically effective amount" will refer to the amount of a biologically active substance required to achieve a therapeutic response in a subject. Amounts effective for this use will depend on: the desired therapeutic effect; the potency of the biologically active substance; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; Physician's judgment.

For example, if epinephrine is the biologically active substance in the solid dosage form of the present invention, then the actual dosage strength of epinephrine may vary depending on the nature of the antiallergic/antiallergic agent and due to the provision and administration of the antihyperallergic agent. The potential efficacy of the advantage varies.

The solid dosage form of the present invention is orally administered to a subject. Solid dosage forms for oral administration include wafers, capsules, tablets, pills, powders, pellets, films and granules. Preferably, the solid dosage form is administered sublingually. Preferably, the solid dosage form is a fast dissolving solid dosage form.

The incorporation of any commonly employed excipients (such as those previously listed) and generally 0.1% to 95% of the biologically active substance, and more preferably 0.1% to 75% of the substance will form a pharmaceutically acceptable compound for oral administration. Accepted non-toxic solid dosage forms.

Although the solid dosage forms of the present invention may be administered as wafers, tablets, capsules; pills; powders; pellets; granules; or films, the oral dosage forms of the present invention are also suitable for use with jet or ultrasonic nebulizers, And will generally include solid dosage forms suspended in water. Dosage forms of the invention may also include buffers and simple sugars (eg, for protein stabilization and regulation of osmotic pressure). Nebulizer formulations may also contain surfactants to reduce or prevent surface-induced aggregation of the compound caused by atomization of the solution in forming the aerosol. Preferably, the solid dosage form is a fast dissolving solid dosage form.

Nebulization of a solid dosage form should preferably not leave a detectable residue of the dosage form in the oral cavity by the patient. Rapidly dissolving bioactive substances in aerosol formulations should be rapidly absorbed by diffusion through the oral mucosa and directly into the systemic blood circulation.

According to another aspect of the present invention there is provided a solid dosage form suitable for releasing in the oral cavity an active substance that binds to one or more adrenergic receptors, wherein said dosage form comprises:

(a) active substances that bind to one or more adrenergic receptors, and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. Alternatively, epinephrine may be provided in the form of: analogs and compounds related to adrenaline, such as norepinephrine, isoproterenol; or sympathomimetic agents, such as tyramine, ephedrine, pseudoephedrine, amphetamine hetamine, salbutamol, and terbutaline.

In one embodiment, the active substance that binds to one or more adrenergic receptors, such as epinephrine, is present in an amount by dry weight of the solid dosage form selected from the group consisting of: 0.01 to 95%; 0.1 to 75% and 1 to 45%.

In another embodiment, the dosage form comprises:

(a) 0.01 to 95 (dry)% by weight of active substances that bind to one or more adrenergic receptors;

(b) between 2 and 17 (dry) weight % amylopectin;

(c) between 0.01 and 50 (dry)% by weight of at least one matrix-forming agent;

(d) between 0.01 and 40 (dry) weight percent filler;

(e) between 0.01 and 10 (dry) weight percent amino acids; and

(f) between 0.01 and 20 (dry) weight % glycol/surfactant

(g) between 0.01 and 60 (dry) weight percent carbohydrates;

(h) between 0.1 and 1 (dry)% by weight solid buffer reagent;

(i) between 0.01 and 20 (dry) weight percent absorption enhancers

In a highly preferred embodiment, the invention provides a solid dosage form suitable for the release in the oral cavity of an active substance that binds to one or more adrenergic receptors, such as epinephrine, wherein said dosage form comprises:

(a) active substances that bind to one or more adrenergic receptors; and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity, wherein the dosage form comprises 0.25% sodium carbonate, 0.50% sodium carboxymethylcellulose, 1.25% PEG 2000, 2.49% glycine, 2.49% microcrystalline cellulose; 12.49% branched Starch, 24.98% lactose, 2.00% glyceryl trinitrate, and 37.46% mannitol were used as dry weight of the solid dosage form and did not result in substantial detectable levels of residue remaining in the patient's mouth. Preferably, the solid dosage form is a fast dissolving solid dosage form.

In another embodiment, the dosage form comprises an active substance (such as epinephrine) that binds to one or more adrenergic receptors in an amount selected from the group consisting of: 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; 35mg, 40mg, 45mg, 50mg, 60mg and 100mg.

According to another aspect of the present invention there is provided a solid dosage form suitable for releasing at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the oral cavity, wherein said dosage form comprises:

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

In one embodiment, at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is present in an amount by dry weight of the solid dosage form selected from the group consisting of: 0.01 to 95%; 0.1 to 75% and 1 to 45%.

In another embodiment, the dosage form comprises:

(a) 0.01 to 95 (dry) weight % of at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor;

(b) between 2 and 17 (dry) weight % amylopectin;

(c) between 0.01 and 50 (dry)% by weight of at least one matrix-forming agent;

(d) between 0.01 and 40 (dry) weight percent filler;

(e) between 0.01 and 10 (dry) weight percent amino acids; and

(f) between 0.01 and 20 (dry) weight % glycol/surfactant

(g) between 0.01 and 60 (dry) weight percent carbohydrates;

(h) between 0.1 and 1 (dry)% by weight solid buffer reagent;

(i) between 0.01 and 20 (dry) weight percent absorption enhancers

In a highly preferred embodiment, the present invention provides a solid dosage form suitable for releasing at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in the oral cavity, wherein said dosage form Include:

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor; and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity, wherein the dosage form comprises 0.29% sodium carbonate, 0.59% sodium carboxymethylcellulose, 1.48% PEG 2000, 2.97% glycine, 5.93% microcrystalline cellulose; 14.84% branched Starch, 29.67% lactose, and 44.23% mannitol were used as dry weight of the solid dosage form and did not result in substantially detectable levels of residue remaining in the patient's mouth. Preferably, the solid dosage form is a fast dissolving solid dosage form.

In another embodiment, the dosage form comprises at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor in an amount selected from the group consisting of: 5 mg; 10 mg; 15 mg; 20 mg; 25mg; 30mg; 35mg, 40mg, 45mg, 50mg, 60mg and 100mg.

According to another aspect of the present invention, there is provided a solid dosage form suitable for releasing an N-methyl-D-aspartate receptor antagonist in the oral cavity, wherein said dosage form comprises:

(a) N-methyl-D-aspartate receptor antagonists, and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

In one embodiment, the N-methyl-D-aspartate receptor antagonist is present in an amount by dry weight of the solid dosage form selected from the group consisting of: 0.01 to 95%; 0.1 to 75% and 1 to 45%.

In another embodiment, the dosage form comprises:

(a) 0.01 to 95 (dry)% by weight of an N-methyl-D-aspartate receptor antagonist;

(b) between 2 and 17 (dry) weight % amylopectin;

(c) between 0.01 and 50 (dry)% by weight of at least one matrix-forming agent;

(d) between 0.01 and 40 (dry) weight percent filler;

(e) between 0.01 and 10 (dry) weight percent amino acids; and

(f) between 0.01 and 20 (dry) weight % glycol/surfactant

(g) between 0.01 and 60 (dry) weight percent carbohydrates;

(h) between 0.1 and 1 (dry)% by weight solid buffer reagent;

(i) between 0.01 and 20 (dry) weight percent absorption enhancers

In a highly preferred embodiment, the present invention provides a solid dosage form suitable for delivery of an N-methyl-D-aspartate receptor antagonist in the oral cavity, wherein said dosage form comprises:

(a) N-methyl-D-aspartate receptor antagonists; and

(b) at least one matrix forming agent,

wherein the dosage form substantially dissolves in the oral cavity, wherein the dosage form comprises 0.25% sodium carbonate, 0.50% sodium carboxymethylcellulose, 1.25% PEG 2000, 2.49% glycine, 2.49% microcrystalline cellulose; 12.49% branched Starch, 24.98% lactose, and 37.46% mannitol were included as dry weight of the solid dosage form and did not result in substantially detectable levels of residue left in the patient's mouth. Preferably, the solid dosage form is a fast dissolving solid dosage form.

In another embodiment, the dosage form comprises an N-methyl-D-aspartate receptor antagonist selected from the group consisting of: 5 mg; 10 mg; 15 mg; 20 mg; 25 mg; 30 mg; 35 mg, 40 mg, 45 mg, 50mg, 60mg and 100mg.

In another embodiment, the solid dosage form provides reduced burning, irritation and/or discomfort on application and/or swallowing compared to conventional dosage forms.

In another embodiment, the dosage form is suitable for delivery via the oral mucosa and into the systemic blood circulation.

According to another aspect of the present invention there is provided a wafer comprising a solid dosage form adapted to release a biologically active substance in the oral cavity. Preferably, the solid dosage wafer is an instant solid dosage wafer. Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors Substances and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. The wafer may be accompanied by instructions for its use.

Preferably, once placed in the oral cavity, the solid dosage form wafer substantially dissolves within a time period selected from the group consisting of less than 2 minutes, less than 1 minute, less than 50 seconds, less than 40 seconds, less than 30 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, less than 7.5 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds. Preferably, the solid dosage wafer is an instant solid dosage wafer.

More preferably, once placed in the oral cavity, the solid dosage form wafer completely dissolves within a time period selected from the group consisting of: less than 2 minutes after administration of the dosage form; less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30 seconds; less than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3 seconds; and less than 2 seconds. Preferably, the solid dosage wafer is an instant solid dosage wafer.

Further features of the invention provide solid dosage form wafers of the invention, wherein the dosage form substantially dissolves in the oral cavity without leaving detectable residues of the dosage form in the oral cavity. Preferably, the solid dosage wafer dissolves completely after oral, preferably sublingual, administration to a patient. Thus, the subject does not have an imperative to swallow the wafer dosage form, and thus the bioactive substance bypasses the gastrointestinal and hepatic first-pass effects, and is absorbed directly into the systemic circulating blood. Preferably, the solid dosage wafer is an instant solid dosage wafer.

pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising the solid dosage form of the present invention. Preferably, the solid dosage form is a fast dissolving solid dosage form.

The pharmaceutical compositions of the present invention may be formulated to additionally contain said substances in usual amounts as conventional additives or supplementary ingredients. The compositions can be in the form of solids, liposomes, or other ordered structures suitable for high drug concentrations suitable for oral delivery. Preferably, the pharmaceutical composition is formulated to dissolve rapidly in the oral environment.

In one embodiment, the composition may be formulated substantially free of preservatives, physiological or mucosal absorption enhancers, or propellants. In an alternative embodiment, the compositions may be formulated to contain preservatives, physiological or mucosal absorption enhancers, or propellants.

method

According to another aspect of the present invention, there is provided a method for producing a solid dosage form of the present invention, comprising the steps of:

a) combining at least one matrix-forming agent with a biologically active substance to form a mixture; and

b) lyophilizing said mixture to form said solid dosage form.

Preferably, the solid dosage form is a fast dissolving solid dosage form.

There is also provided a method of producing a solid dosage form of the invention comprising the steps of:

a) combining at least one matrix-forming agent with an active substance that binds to one or more adrenergic receptors to form a homogeneous mixture; and

b) lyophilizing said mixture to form said solid dosage form.

Preferably, the solid dosage form is a fast dissolving solid dosage form.

There is also provided a method of producing a solid dosage form of the invention comprising the steps of:

a) combining at least one matrix-forming agent with at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor to form a homogeneous mixture; and

b) lyophilizing said mixture to form said solid dosage form.

c) Preferably, the solid dosage form is a fast dissolving solid dosage form.

There is also provided a method of producing a solid dosage form of the invention comprising the steps of:

a) combining at least one matrix-forming agent with an N-methyl-D-aspartate receptor antagonist to form a homogeneous mixture; and

b) lyophilizing said mixture to form said solid dosage form.

Preferably, the solid dosage form is a fast dissolving solid dosage form.

Preferably, the method provides a solid dosage form, wherein the dosage form substantially dissolves in the oral cavity without leaving detectable residues of the dosage form in the oral cavity by the subject. Preferably, the solid dosage form is a fast dissolving solid dosage form.

Preferably, the method of the invention produces a solid dosage form which, once placed in the oral cavity, substantially dissolves within a time period selected from the group consisting of: less than 2 minutes, less than 1 minute, less than 50 seconds after administration , less than 40 seconds, less than 30 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, less than 7.5 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds.

More preferably, once placed in the oral cavity, the solid dosage form completely dissolves within a time period selected from the group consisting of: less than 2 minutes; less than 1 minute; less than 50 seconds; less than 40 seconds; less than 30 seconds after administration of the dosage form ; less than 20 seconds; less than 15 seconds; less than 10 seconds; less than 7.5 seconds; less than 5 seconds; less than 4 seconds; less than 3 seconds; and less than 2 seconds.

In a preferred embodiment of the invention, the mixture comprising the matrix forming agent and the biologically active substance is metered (by weight or volume) into pre-formed plastic or aluminum blister molds (individual doses). The blister molds are placed into a freeze dryer for 24 hours, and the resulting instant solid dosage form is then sealed with aluminum or plastic foil to prevent moisture absorption. Preferably, freeze drying techniques are used to remove the solvent from the blister mold. Sealing solid dosage forms into plastic or aluminum foil prevents or reduces moisture absorption.

Preferably, the method of the invention forms a solid dosage form that is a wafer. Preferably, the solid dosage wafer is an instant solid dosage wafer.

In one embodiment of the invention, the method may entail adjusting the pH of the mixture to a pH in the range between 3.0 and 8.0, preferably between 6.4 and 7.8. The pH can be adjusted, if necessary, by using acids such as hydrochloric acid, phosphoric acid, or citric acid; or basic compounds such as sodium hydroxide, sodium dihydrogenphosphate dehydrate, disodium hydrogenphosphate, sodium bicarbonate, and sodium carbonate.

In another embodiment, the method may include the step of using a solvent such as water. If water is used as solvent, it is preferably removed by freeze drying.

pill box

The present invention also provides a kit comprising the solid dosage form of the present invention and instructions for its use.

In another aspect of the present invention, a kit is provided, comprising:

a) a solid dosage form, wherein the dosage form comprises:

(i) at least one biologically active substance, and

(ii) at least one matrix forming agent, and

b) its instruction manual

wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form.

Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

treatment method

Therapeutic uses of the solid dosage forms of the present invention include pain relief, anti-inflammatory activity, migraine treatment, asthma treatment and treatment of other conditions requiring administration of bioactive substances with high bioavailability and rapid activity.

Accordingly, the invention provides a method of treating a disease or condition in a patient comprising the step of administering to said patient a pharmaceutical composition comprising a solid dosage form of the invention. Preferably, the solid dosage form is a fast dissolving solid dosage form.

One major area when rapid bioavailability of bioactive substances is required is in pain relief. Adjunct analgesics such as cyclooxygenase inhibitors (aspirin-related drugs) or opioids can be prepared as medicaments according to the invention. Alternatively, N-methyl-D-aspartate receptor antagonists may be used in pain relief and anesthesiology. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. N-methyl-D-aspartate receptor antagonists can also be administered for the purpose of depression treatment, addiction treatment.

Accordingly, the present invention provides a method for providing pain relief comprising the step of: administering to a patient a pharmaceutical composition comprising a solid dosage form of the present invention comprising an N-methyl-D-aspartate receptor antagonist .

The present invention also provides a method for providing anesthesia comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the present invention comprising an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

The present invention also provides a method for treating depression, which comprises the steps of: administering to a patient a pharmaceutical composition comprising a solid dosage form of the present invention containing an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

The present invention also provides a method for treating addiction, comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the present invention containing an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

N-methyl-D-aspartate receptor antagonists may also be administered for the purpose of treating epileptic seizures. In one embodiment, the seizure is caused by epilepsy. In another embodiment, the epilepsy is selected from the group consisting of benign Rolandicepilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy (epilepsy petit mal), thermal bath epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Dravet syndrome ), progressive myoclonic epilepsy, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, menstruation epilepsy, Jacksonian seizure disorder, Lafora disease, and photosensitive epilepsy. In another embodiment, the seizure is selected from the group consisting of non-spastic status epilepticus and spastic status epilepticus.

Accordingly, the present invention provides a method for treating epileptic seizures, comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the present invention comprising an N-methyl-D-aspartate receptor antagonist. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine.

The treatment of cardiovascular disease may also benefit from the bioactive substances in the solid dosage form of the present invention, such as the treatment of angina pectoris, and in particular molsidomine may benefit from improved bioavailability. In another example, epinephrine may be administered in solid dosage form to treat acute cardiovascular events, such as cardiac arrest or cardiac rhythm disorders. Alternatively, other active substances that bind to one or more adrenergic receptors, such as norepinephrine, may be used in solid dosage forms for the treatment of cardiovascular events.

Other therapeutic uses of the bioactive substances in the solid dosage forms of the invention include the treatment of alopecia, sexual dysfunction or psoriasis. If the solid dosage form of the invention is used to treat sexual dysfunction, then the dosage form will preferably contain a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Accordingly, the present invention provides a method for treating sexual dysfunction comprising the step of administering to a patient a drug comprising at least one inhibitor of cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5). The pharmaceutical composition in solid dosage form of the present invention. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Another use of the solid dosage form of the present invention containing a cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is in the treatment of pulmonary hypertension. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Accordingly, the present invention provides a method for treating pulmonary hypertension comprising the step of administering to a patient a drug comprising at least one cyclic guanosine monophosphate (cGMP) type 5 phosphodiesterase (PDE5) inhibitor The pharmaceutical composition in solid dosage form of the present invention. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Other therapeutic uses of the bioactive substances in the solid dosage forms of the invention include allergy relief and allergy treatment. Such conditions benefit from the rapid absorption of biologically active substances, such as epinephrine and other active substances, that bind to one or more adrenergic receptors.

Accordingly, the present invention provides a method for the treatment of allergy comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the invention comprising an active substance that binds one or more adrenergic receptors. The invention further provides a method for the treatment of allergy comprising the step of administering to a patient a pharmaceutical composition comprising a solid dosage form of the invention comprising an active substance that binds one or more adrenergic receptors. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine or an epinephrine salt.

Preferably, the method of treatment comprises administering to a patient a solid dosage form of the invention, wherein said dosage form is administered sublingually. Preferably, the solid dosage form is a fast dissolving solid dosage form.

·Administration

The solid dosage forms of the invention are suitable for oral administration to a subject. As discussed above, dosage forms comprise at least one biologically active substance. Thus, the biologically active substance is delivered to the subject through the oral mucosa and into the systemic blood system within a relatively short period of time. Preferably, the solid dosage form is a fast dissolving solid dosage form.

In a preferred embodiment, the effective plasma concentration of the biologically active substance is achieved within a period of up to two hours, preferably within 30 minutes, 20 minutes, 15 minutes or less than 15 minutes. Most preferably, the effective plasma concentration of the biologically active substance is achieved within a time period of 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes or 2 minutes. For example, solid dosage forms of the invention in the form of sublingual fentanyl wafers can result in detectable plasma fentanyl within 2 to 10 minutes after administration, in most cases within 5 minutes. In other examples, the epinephrine solid dosage form of the present invention can be therapeutic within 5 minutes; the sildenafil solid dosage form within 20 minutes, and the ketamine fast dissolving solid dosage form can be therapeutic within 10 minutes.

In another embodiment, the dosage form provides the patient with a peak plasma concentration ( _Cmax ) of the biologically active substance selected from the group consisting of: 25 ng/ml; 30 ng/ml; 40 ng/ml; 50 ng/ml; 60 ng/ml; 70 ng 130ng/ml; 140ng/ml; 150ng/ml; 160ng/ml; 170ng/ml; 180ng/ml; 190ng/ml ; and 200 ng/ml.

The solid dosage form of the invention in the form of a sublingual wafer produces a much lower _Cmax when compared to intravenous injection, which reduces the toxicity of the administered biologically active substance. For example, in the phase I clinical trial of sublingual fentanyl wafers, the C _max (5 minutes) of 100 μg fentanyl intravenous infusion was 1451.0 pg/mL, however, the C _max of 100 μg fentanyl wafers Only 219.3pg/mL. Similarly, in a phase I clinical trial of sublingual ketamine wafers, the _Cmax (30 minutes) of an intravenous infusion of 10 mg ketamine was 128.1 ng/mL and the _Cmax of 25 mg ketamine wafers was 71.1 ng/mL.

In another embodiment, the solid dosage form has a median _tmax of the biologically active substance selected from the group consisting of: between 5 minutes and 90 minutes; between 10 minutes and 75 minutes; between 15 minutes and 60 minutes between 30 minutes and 50 minutes; between 40 minutes and 50 minutes; and 45 minutes. For example, a solid dosage form of the invention in the form of a 25 mg ketamine wafer may have a _Tmax of 45 minutes.

In a highly preferred embodiment, the dosage form provides a first detectable plasma concentration of the biologically active substance within a time selected from the group consisting of: within 15 minutes; within 14 minutes; within 13 minutes; within 12 minutes ;in 11 minutes;in 10 minutes;in 9 minutes;in 8 minutes;in 7 minutes;in 6 minutes;in 5 minutes;in 4 minutes;in 3 minutes;in 2 minutes ; and within 1 minute. For example, following sublingual administration with a dosage form of the invention, the first detectable plasma fentanyl concentration can be observed between 2 and 10 minutes after administration.

Preferably, the dosage form provides a median bioavailability of the biologically active substance in the patient selected from the group consisting of: between 10 and 60%; between 20 and 40%; between 25 and 35%; at between 28 and 30%; and 28%. For example, a solid dosage form may provide a median bioavailability in patients of 28% of an N-methyl-D-aspartate receptor antagonist at a dose of 25 mg of the antagonist. The solid dosage form also provides a median bioavailability of 29% of sublingual ketamine where the dose of ketamine is 25 mg.

In another embodiment, the solid dosage form provides the patient with therapeutically effective plasma levels of the biologically active substance over a period of time selected from the group consisting of: more than 30 minutes, 30 minutes, 25 to 30 minutes, 20 to 25 minutes, 15 to 20 minutes, 10 to 15 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes or 2 minutes.

Subjects receiving solid dosage forms of the invention can be animals or humans. When the subject is human, it can be an adult or a child, including older adults and infants. In particular, the subject can be a subject who is unable to swallow or has difficulty swallowing.

The present inventors have surprisingly found that the addition of sodium carboxymethylcellulose improves the dissolution rate of solid dosage forms. When the amount of sodium carboxymethylcellulose is between about 0.1% and 15% by dry weight of the dosage form, the dosage form releases the active agent rapidly without leaving a residue in the oral cavity. Furthermore, the use of gelatin is avoided and thus leaves little or no undesirable residue in the oral cavity after application. It is also advantageous to add lactose and/or mannitol to the solid dosage forms of the invention.

use

Also provided is the use of a solid dosage form suitable for releasing a biologically active substance in the oral cavity for the manufacture of a medicament for the treatment of a disease or condition, wherein the dosage form comprises:

(a) at least one biologically active substance, and

(b) at least one matrix-forming agent, wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form.

Preferably, the biologically active substance is selected from the list comprising: at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, activity binding one or more adrenergic receptors substances, and N-methyl-D-aspartate receptor antagonists. Preferably, the N-methyl-D-aspartate receptor antagonist is selected from the list comprising: dextromethorphan, dextrorphan or ketamine. Preferably, the active substance that binds to one or more adrenergic receptors is epinephrine epinephrine or a salt of epinephrine. Preferably, the cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a pharmaceutically acceptable salt thereof. Preferably, the sildenafil salt is sildenafil citrate.

Preferably, the disease or condition is selected from the list comprising: pain, depression, addiction, inflammation, migraine, asthma, epilepsy, acute cardiovascular events (such as cardiac arrest or cardiac rhythm disorders), angina, alopecia, Sexual dysfunction, psoriasis, pulmonary hypertension, allergies/hypersensitivity and providing anesthesia.

Accordingly, there is provided the use of a solid dosage form suitable for releasing a biologically active substance in the oral cavity for the manufacture of a medicament for the treatment of a disease or condition, wherein said dosage form comprises:

(a) at least one cyclic guanosine monophosphate (cGMP) phosphodiesterase type 5 (PDE5) inhibitor, and

(b) at least one matrix-forming agent, wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the disease or condition is selected from the list comprising: sexual dysfunction, pulmonary hypertension.

Use of a solid dosage form suitable for releasing a biologically active substance in the oral cavity for the manufacture of a medicament for treating a disease or condition, wherein the dosage form comprises:

(a) N-methyl-D-aspartate receptor antagonists, and

(b) at least one matrix-forming agent, wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the disease or condition is selected from the list comprising: pain, depression, addiction, migraine, epilepsy and provision of anesthesia.

Use of a solid dosage form suitable for releasing a biologically active substance in the oral cavity for the manufacture of a medicament for treating a disease or condition, wherein the dosage form comprises:

(a) active substances that bind to one or more adrenergic receptors, and

(b) at least one matrix-forming agent, wherein the dosage form substantially dissolves in the oral cavity. Preferably, the solid dosage form is a fast dissolving solid dosage form. Preferably, the disease or condition is selected from the list comprising: acute cardiovascular events (such as cardiac arrest or cardiac rhythm disturbance), angina pectoris, allergies or anaphylaxis.

General

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those expressly described. It is to be understood that the invention includes all such changes and modifications. The invention also includes all of the steps, features, compositions and materials referred to or indicated in the specification, individually or collectively, and any and all combinations of steps or features or any two or more of the steps or features.

The present invention is not to be limited in scope by the particular embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions and methods are expressly within the scope of the invention as described herein.

The invention described herein may include one or more ranges of values (eg, size, concentration, etc.). Numerical ranges are to be understood to include all values within the range, including the values defining the range and values adjacent to the range which result in the same or substantially the same value as the values immediately adjacent the boundaries defining the range .

The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference. Incorporation does not constitute an admission that any reference forms prior art or forms part of the common general knowledge of those skilled in the art to which the invention pertains.

Throughout this specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising") will be understood to imply the inclusion of a stated integer or group of integers, however, Any other integer or any other set of integers is not excluded. It should also be noted that in this disclosure, and particularly in the claims and/or paragraphs, terms such as "comprises" and the like may have the meaning ascribed to them under US Patent Law; for example they may mean "comprises" and the like.

A "therapeutically effective amount" as used herein with respect to methods of treatment, and in particular dosages of a drug, shall mean that dose which provides a specific pharmacological response of the administered drug in a large number of subjects in need of such treatment. It is emphasized that a "therapeutically effective amount" administered to a particular subject in a particular situation is not always effective in treating the diseases described herein, although such dosage is considered a "therapeutically effective amount" by those skilled in the art. It is further understood that in certain instances drug doses are measured as oral doses, or by reference to drug levels as measured in blood.

The term "inhibit" is defined to include its generally accepted meaning, which includes inhibiting, arresting, halting and reducing, halting or reversing the progression or severity, as well as such effects on the resulting symptoms. Accordingly, the present invention includes both medically therapeutic and prophylactic administration as appropriate.

The term "biologically active substance" is defined to mean a biologically active compound or a substance comprising a biologically active compound. In this definition, compounds are generally considered to refer to distinct chemical entities for which one or more chemical formulas may be used to describe the substance. Such compounds will often, though not necessarily, be identified in the literature by a unique classification system such as a CAS number. Some compounds may be more complex and have mixed chemical structures. For said compounds, they may have only empirical formulas or be identified qualitatively. The compound will generally be a pure substance, but it would be expected that as much as 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be other impurities, etc. Examples of biologically active compounds are, but are not limited to: fungicides, insecticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, nutraceuticals, pharmaceutical actives , biological agents, amino acids, proteins, peptides, nucleotides, nucleic acids, additives, food and food ingredients and their analogues, homologues and primary derivatives. A biologically active compound-containing substance is any substance that has a biologically active compound as one of its components. Examples of substances containing biologically active compounds are, but not limited to, pharmaceutical preparations and products, cosmetic preparations and products, industrial preparations and products, agricultural preparations and products, food, seeds, cocoa and cocoa solids, coffee, herbal preparations, spices, Other plant material, minerals, animal products, shells and other framework materials.

Any of the terms "biologically active", "active", "active substance" shall have the same meaning as biologically active substance.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for oral administration.

Brief description of the drawings

Figure 1 Scanning electron micrographs of the surface of wafers from lot numbers 071501B and 071502B.

Figure 2 Scanning electron micrographs of the surface of wafers from lot numbers 0820A and 0820B.

Figure 3 is a scanning electron micrograph of the surface of wafer from Lot 0905MD.

Figure 4 Scanning electron micrographs of cross-sections of wafers from lot numbers 071501B and 071502B.

Figure 5 Scanning electron micrographs of cross-sections of wafers from lot numbers 0820A and 0820B.

Figure 6 is a scanning electron micrograph of a cross-section of a wafer from Lot 0905MD.

Figure 7 Powder X-ray Diffraction Spectrum of wafers from lot numbers 071501A and 071502B.

Figure 8 Powder X-ray Diffraction Spectrum of wafers from lot numbers 0820A and 0820B.

Figure 9 Powder X-ray Diffraction Spectrum of wafer from Lot 0905MD.

Figure 10 [A] standard midazolam samples (n=3) at 4.05 μg/mL; [B] midazolam powder dissolution samples at 1 minute and 5 minutes; [C] midazolam at 10 minutes Dazolam powder dissolution sample; [D] 15 min midazolam powder dissolution sample; and [E] typical HPLC chromatogram of standard midazolam sample at 8.1 μg/ml.

Figure 11 Typical HPLC chromatograms of dissolution wafer sample S1 at 45 seconds and 1 minute.

Figure 12 Typical HPLC chromatogram of dissolution wafer sample S1 at 10 minutes.

Figure 13 Typical HPLC chromatograms of dissolution wafer sample S2 at 5 and 10 minutes.

Figure 14 Typical HPLC chromatograms of dissolution wafer sample S2 at 30 seconds and 2 minutes.

Figure 15 Typical HPLC chromatograms of dissolution wafer sample S3 at 20 seconds and at 1 minute.

Figure 16 Typical HPLC chromatogram of a standard midazolam sample at 1.01 μg/mL.

Figure 17 Typical HPLC chromatogram of midazolam powder dissolution sample at 30 seconds.

Figure 18 Typical HPLC chromatograms of dissolution wafer 1 at 1 minute and 5 minutes.

Figure 19 Typical HPLC chromatograms of dissolution wafer 1 at 5, 10 and 15 minutes.

Fig. 20 Typical HPLC chromatogram of drug loading test wafer sample No. 1.

Figure 21 Typical HPLC chromatogram of dissolution wafer 2 at 30 seconds.

Figure 22 Typical HPLC chromatograms of dissolution wafer 2 at 1 minute and 5 minutes.

Figure 23 Typical HPLC chromatograms of dissolution wafer 2 at 10, 15 and 30 minutes.

Fig. 24 Typical HPLC chromatogram of No. 2 drug loading test wafer sample.

Figure 25 Typical HPLC chromatogram of dissolution wafer 3 at 30 seconds.

Figure 26 Typical HPLC chromatograms of dissolution wafer 3 at 1 minute and 5 minutes.

Figure 27 Typical HPLC chromatograms of dissolution wafer 3 at 10 and 15 minutes.

Figure 28 Typical HPLC chromatograms of dissolution wafer 3 at 30, 45 and 60 minutes.

Figure 29 Typical HPLC chromatogram of sample No. 3 drug loading test wafer.

Figure 30 Standard HPLC calibration curve for midazolam (1 to 32.4 μg/mL).

Figure 31 Cumulative concentration of midazolam released from wafer and midazolam powder in phosphate buffered saline (pH 6.8) at 37°C.

Figure 32 Standard HPLC calibration curve for fentanyl (0.5 to 10 μg/mL).

Figure 33 is the dissolution profile (n=4) of fentanyl wafers in phosphate buffer solution (pH 6.8) at 37°C.

Figure 34A-E Representative HPLC chromatograms of dissolution samples 1-3 of fentanyl wafer at sampling times 0.5, 1, 5, 10, 15 and 20 minutes.

Figure 35A-J Representative HPLC chromatograms of dissolution samples 4-6 of fentanyl wafer at sampling times 1, 2, 3, 4, 5, 7 and 10 minutes.

Figure 36 Scanning electron micrograph of the surface of a blank fast-dissolving form.

Figure 37 Scanning electron micrograph of the surface of ketamine instant form.

Figure 38 Powder X-ray Diffraction Spectrum of Blank Fast Dissolving Form.

Figure 39 Powder X-ray Diffraction Spectrum of Ketamine Powder.

Figure 40 Powder X-ray Diffraction Spectrum of Ketamine Instant Dissolution Form.

Figure 41 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 1 minute.

Figure 42 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 3 minutes.

Figure 43 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 5 minutes.

Figure 44 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 7 minutes.

Figure 45 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 10 minutes.

Figure 46 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 15 minutes.

Figure 47 is a typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 20 minutes.

Figure 48 Typical HPLC chromatogram of dissolution ketamine wafer sample S2 at 30 minutes.

Figure 49 Standard HPLC calibration curve for ketamine hydrochloride (5 to 100 μg/mL).

Figure 50 Typical HPLC chromatogram of a sample of ketamine wafer for drug loading test No. 1.

Fig. 51 Dissolution curve (n=3) of ketamine wafer in phosphate buffer solution (pH 6.8) at 37°C.

Figure 52 Overlapped geometric means of individual RS ketamine plasma concentrations over the entire sampling period following administration of a 10 mg dose to 8 healthy volunteers during a 30 minute intravenous infusion.

Figure 53 Overlaid geometric means of individual RS ketamine plasma concentrations during the first 12 hours following administration of a 10 mg dose to 8 healthy volunteers during a 30 minute intravenous infusion.

Figure 54 Overlapped geometric means of individual RS ketamine plasma concentrations for the entire sampling period following administration of a 25 mg sublingual dose to 8 healthy volunteers.

Figure 55 Overlay geometric means of individual RS ketamine plasma concentrations during the first 12 hours following a 25 mg sublingual dose to 8 healthy volunteers.

Figure 56 Individual (S = subject randomization number) _tmax for RS ketamine following a 25 mg sublingual dose to 8 healthy volunteers.

Figure 57 RS ketamine individual (S=recipient Randomization number of subjects) AUC _INF .

Figure 58 Individual (subject randomization number) clearance (CL) of RS ketamine following a 10 mg dose to 8 healthy volunteers during a 30 minute intravenous infusion.

Figure 59 RS ketamine individual (S=subject randomization number) terminal half-life t _1/2 .

Figure 60 Individual estimates of % bioavailability (F) for all subjects (S=subject number) following administration of 25 mg RS ketamine to 8 healthy volunteers.

Figure 61 Mood Rating Scale Curve for IV Administration. Elements "alertness" (element 1), "contentedness" (element 2) and "calmness" (element 3) observed following a 30-minute intravenous infusion of 10 mg ketamine in healthy volunteers The mean (SD) score of .

Figure 62 Mood Rating Scale Curve for Sublingual Administration. Mean (SD) scores for the elements "vigilance" (element 1), "peace of mind" (element 2) and "calm" (element 3) observed after sublingual administration of 25 mg ketamine wafers to healthy volunteers.

Figure 63 Modified Likert Local Tolerance Overall Scale

Figure 64 Scanning electron micrograph of the surface of a blank fast-dissolving form.

Figure 65 Powder X-ray Diffraction Spectrum of Blank Fast Dissolving Form.

Figure 66 Powder X-ray Diffraction Spectrum of Sildenafil Powder.

Figure 67 Powder X-ray Diffraction Spectrum of Sildenafil Instant Dissolution Form.

Figure 68 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 1 minute.

Figure 69 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 3 minutes.

Figure 70 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 5 minutes.

Figure 71 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 7 minutes.

Figure 72 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 10 minutes.

Figure 73 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 15 minutes.

Figure 74 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 20 minutes.

Figure 75 Typical HPLC chromatogram of dissolution sildenafil wafer sample S1 at 30 minutes.

Figure 76 Typical HPLC chromatogram of sildenafil wafer sample for drug loading test No. 1.

Figure 77 Standard HPLC calibration curve of sildenafil (5 to 100 μg/mL).

Figure 78 is the dissolution profile (n=4) of sildenafil wafers in phosphate buffer solution (pH 6.8) at 37°C.

FIG. 79 shows a table of demographic characteristics of study volunteers according to Example 4.

Figure 80 is a graph showing the mean (±SEM) plasma concentration (pg/mL) of sublingual fentanyl wafers and IV fentanyl over time. Inset is the zoomed-in curve for the initial 2-h period.

Figure 81 is a graph showing plasma concentration data (pg/mL) of sublingual fentanyl wafers over time for each volunteer (n=22).

Figure 82 shows a table of mean values (±1 SD) for fentanyl plasma pharmacokinetic parameters.

Figure 83 shows a table of comparative literature pharmacokinetic data (mean ± 1 SD) for buccal and sublingual (SL) fentanyl dosage forms.

Example

The invention will now be described with reference to the following non-limiting examples. The descriptions of the examples are in no way limiting of the preceding paragraphs of the specification, but are provided to illustrate the methods and compositions of the invention.

Example 1

The formulations of the invention in the form of solid dosage forms (wafers) were prepared according to the method and ingredients as set forth in Table 1 below:

Table 1: Formula of instant solid dosage form (wafer)

Element amount (g) weight% Sodium Carbonate BP/USP 10 0.075 Sodium Carboxymethyl Cellulose BP/USP 20 0.149 Polyethylene glycol 2000BP/USP 50 0.374 Glycine BP/USP 100 0.747 Microcrystalline Cellulose BP/USP 200 1.495 Pullulan BP/USP 500 3.737 LactoseBP/USP 1000 7.474 Mannitol BP/USP 1500 11.211

Purified water BP/USP 10000 74.738

Add sodium carboxymethylcellulose and pullulan in a portion of purified water by mixing well with a mixer. The mixture was then heated to 50°C for 10 minutes to dissolve the polymer. Once the solution had cooled to room temperature, polyethylene glycol 2000, glycine, sodium carbonate, microcrystalline cellulose, lactose, and mannitol were added individually with stirring to obtain a homogeneous solution. The viscosity of the solution was measured at 25°C using a Brookfield digital viscometer (Brookfield Engineering Laboratories Inc., MA, USA).

The resulting mixture was transferred by pipette and accurately weighed into pre-formed blister packs, then transferred to a freezer (-30°C) for approximately 24 hours. After freezing, samples were freeze-dried (DYNAVAC, Australia) for 24 hours. Store the prepared samples on silica gel in a desiccator at room temperature.

The following other wafer formulations were prepared by the method set forth above. Samples 1 to 6 were basically based on the above formulations with the addition of flavoring and/or coloring agents.

Sample 1. Additionally contained flavoring.

Element amount (g) weight% Sodium carbonate 1 0.08 Sodium carboxymethyl cellulose 2 0.15 polyethylene glycol 2000 5 0.37 orange flavoring 10 0.74 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 7.42 Mannitol 150 11.13 purified water 1000 74.18

Sample 2. Additionally contained a flavoring agent and a pH adjuster (citric acid).

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 citric acid 5 0.37 polyethylene glycol 2000 5 0.37

mint flavoring 10 0.74 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.70 lactose 100 7.39 Mannitol 150 11.09 purified water 1000 73.91

Sample 3. Additional flavoring and coloring agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 polyethylene glycol 2000 5 0.37 grape flavoring 9.9 0.74 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 7.42 Mannitol 150 11.13 purified water 1000 74.18

Sample 4. Additionally contains flavoring, coloring and absorption enhancers.

Element amount (g) weight% FD&C blue 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 β-cyclodextrin 5 0.37 polyethylene glycol 2000 5 0.37 grape flavoring 9.9 0.73 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 7.42 Mannitol 145 10.76 purified water 1000 74.19

Sample 5. Additionally contains coloring and sweetening agents

Element amount (g) weight%

FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 aspartame 5 0.37 polyethylene glycol 2000 5 0.37 cherry flavoring 9.9 0.73 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 7.42 Mannitol 145 10.76 purified water 1000 74.19

Sample 6. Additionally contains colorants and pH regulators

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 sodium bicarbonate 5 0.37 polyethylene glycol 2000 5 0.37 raspberry flavoring 9.9 0.73 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 7.42 Mannitol 145 10.76 purified water 1000 74.19

Various batches of solid dose wafer forms were then prepared based on the formulation shown in Table 1 and also containing midazolam (base) or fentanyl citrate (2.5 mg fentanyl base for 50 wafers with a strength equivalent of 50 μg fentanyl base) as a solid dose wafer form of the biologically active substance. Batch numbers and ingredients are listed in Table 2.

Table 2: Midazolam or Fentanyl Compositions for Study

general observations

No significant difference was found between the use of polyethylene glycol 1000 or polyethylene glycol 2000 in the wafer formulation (results not shown).

The addition of starch produces a hard wafer and is less suitable for the instant solid dosage forms of the present invention.

Weight Uniformity

The weight uniformity of the instant solvent volume wafer format was tested according to the British Pharmacopoeia (BP) 2009 test. Twenty wafers from each formulation listed in Table 2 were individually weighed, and the average weight and relative standard deviation were calculated. All prepared wafers from the different formulations were within the accepted weight variation between 0.25 and 2%.

hardness

The dosage formulations listed in Table 2 were also tested for hardness. The mechanical strength of a tablet is called "hardness". The hardness of the wafers was determined using an Erweka hardness tester (Germany). The hardness values for the different formulations ranged from 0.5 to 4.0 kg. It was observed that the hardness of the formulation increased when Avicel was added to the formulation (results not shown).

Friability

Measures the strength of instant solid dose wafer forms, ie their ability to reduce from a solid mass into smaller fragments. Testing was performed according to the BP 2009 method (i.e. friability of uncoated tablets) using an Erweka friability tester (Germany). A sample of 20 wafers was accurately weighed and placed in the apparatus. A spin time of 4 minutes at 25 rpm was used. The wafer was removed and reweighed, and the percent weight loss was calculated. The weight loss of 20 wafers was found to be in the range of 8 to 20%. Although this weight loss does not meet the BP 2009 standard of approximately 1% weight loss for compressed tablets, no such standard exists for wafers in the BP or USP monographs.

Moisture analysis

Wafers were analyzed for moisture content after lyophilization using an 870 Karl Fisher Titrino Plus (Metrohm Ag, Germany). The results showed that the residual moisture content of the different formulations varied between 1% and 5%.

Scanning Electron Microscopy

Surface morphology and cross-sections of selected wafer preparations were observed using a scanning electron microscope (SEM) (Zeiss, EVO 40XVP, Oxford Instrument, UK). Prepare cross-sectional samples by cutting thin slices of the wafer using a scalpel. The samples were coated with carbon prior to examination. The accelerating voltage was 10 kV.

The SEM images shown in Figures 1 to 6 illustrate the highly porous nature of the wafer, both on the surface and internal structure. Clearly, there were morphological differences between the different formulations. These differences indicate that the excipients used affect the microstructure of the wafer. Furthermore, the microstructure may give an account of different hardness, friability, disintegration time and even dissolution profiles of wafers prepared from different formulations.

Powder X-ray Diffraction (XRD)

X-ray diffraction experiments were performed using a Bruker D8 Advance (Germany) with detector LynEye. The radiation used was nickel filtered CuKα generated using an accelerating voltage of 40 kV and a cathodic current of 40 mA. Samples were scanned over a 2Θ range of 7.5 to 70 degrees and at a count time of 1 second/0.02 degrees.

The physical state of matter in the wafer is evident in the X-ray diffraction spectrum. The spectra of three different formulations as prepared according to Table 2 are shown in Figures 7-9. All powder patterns of the prepared wafers were observed to be dominated by strong scattering peaks at approximately 2Θ of 9.58°, 19, 68° and 20.05°, indicating a crystalline nature. This finding is also supported by data generated from SEM (see Figures 1-6). In fact, the excipients used in the formulation (such as glycine, lactose, mannitol and microcrystalline cellulose) are crystalline in nature. Minimal changes in physical state were observed in the solid dispersion.

Disintegration and Dissolution Analysis

Disintegration and dissolution tests were performed using Apparatus I (BP 2009, rotating basket apparatus). An Erweka dissolution apparatus (Hesenstamm, Germany) was used for both experiments. The temperature of the medium was maintained at 37±0.5°C.

For the disintegration test, the wafers were placed in a cylindrical rotating basket and wetted on the underside by contact with distilled water in a cylindrical container. The total dissolution time for each wafer was recorded and the average calculated.

For dissolution testing wafers containing midazolam as model drug (Lot 0905MD) were used to determine the mechanism of drug release from the system following both the BP basket method and the USP paddle method (see Figure 17). The dissolution medium was 500 mL of phosphate buffered saline (pH close to salivary fluid at 6.8) with paddle rotation speed at 75 rpm. At given intervals (eg, 0.5, 1, 2, 3, 5, 10, 15, 20, and 30 minutes), 2 mL of the solution was sampled and replaced with an equal volume of fresh medium to maintain a constant total volume. Samples were filtered through a 0.2 μm Millipore filter. Released drug was measured by HPLC.

The HPLC system consisted of a Waters 1525 pump, a Waters Symmetry C ₁₈ column (5 μm, 150×4.6 mm) and a Waters UV 484 detector. The mobile phase was acetonitrile:10 mM ammonium acetate buffer (40:60, v/v, pH 4.10) and the flow rate was 1.2 ml/min at ambient temperature. A peak at 220 nm was recorded and the limit of quantitation was about 1 ng/ml. The calibration curve (six-point calibration) for concentrations 1-32.4 μg/mL was linear [y=870714x+52057 (r=0.9998), y represents the peak area of midazolam, and x represents the concentration of the sample].

A standard HPLC calibration curve for midazolam is shown in FIG. 30 . The results shown in Figure 31 demonstrate that the average disintegration time is less than 15 seconds; and the dissolution studies also indicate that midazolam has a fast release rate. Almost 75% of the midazolam had dissolved within 1 minute. Crude midazolam powder was significantly slower. This may indicate a change in the crystalline form of midazolam in the wafer, which is also evident in X-rays. X-ray spectroscopy indicated the amorphization of midazolam during the freeze-drying process.

The results of the HPLC analysis of various samples of the formulations as prepared according to Table 1 are shown in Figures 11 to 29 . Figures 10A to 10E illustrate HPLC of standard midazolam samples and midazolam powder dissolution samples. Figures 11 to 16 are HPLC chromatograms of dissolution wafer samples 1 to 3 (S1, S2 and S3, BP basket method). Briefly, samples 1, 2 and 3 were prepared according to Table 1 and were triplicate samples with the same formulation. Figure 17 illustrates the HPLC chromatogram of batch 0905MD containing midazolam as a model drug.

Figures 18 to 29 reflect the HPLC chromatograms (USP paddle method) of three additional dissolution wafer samples. As discussed above, the dissolution rate of wafers containing the test drug midazolam was measured. Samples were taken at 0.5 minutes, 1 minute, 5 minutes, 10 minutes and 15 minutes.

The results for Wafers 1 to 3 (Lot 0905MD) over these time frames are shown in Figures 18 to 29. Three additional wafers (Lot 0905MD) were also tested for drug loading.

It was shown that the wafer of the invention is able to dissolve completely in about 15 seconds and leaves no residue.

Wafers (Lot 1003FEN) containing fentanyl as a model drug were used to determine the mechanism of drug release from the system following the BP basket method. The dissolution rate of wafers was determined in a small volume (10 mL of phosphate buffered saline, pH 6.8) at a basket rotation speed of 50 rpm. At given intervals (eg, 0.5, 1, 2, 3, 4, 5, 7, 10, and 15 minutes), 0.5 mL of the solution was sampled and replaced with an equal volume of fresh medium. Released drug was measured by HPLC.

The mobile phase was methanol:0.4% phosphoric acid (50:50, v/v, pH 2.3) and the flow rate was 1.2 ml/min at ambient temperature. The monitoring wavelength is at 210nm. The calibration curve (eight-point calibration) for concentrations 0.5-10 μg/mL was linear [y=316668x+4675.7, (r=0.9999), y represents the peak area of fentanyl, and x represents the concentration of the sample]. The assay standard curve is shown in FIG. 32 .

The prepared fentanyl wafers (Lot 1003FEN) showed a weight variation of ±2.55% and the average percent fentanyl content of the wafers was 91.32% (BP standard 85 to 115% for uniformity content limits). The average disintegration time was less than 15 seconds; and dissolution studies also indicated that the fentanyl had a rapid release rate. Almost 90% of the fentanyl was dissolved within 1 minute. The dissolution profile is presented in Figure 33.

The HPLC chromatograms of six dissolution samples of fentanyl wafers were collected and shown in Figures 34A-E (samples 1-3) and Figures 35A-J (samples 4-6). Each test was performed at 0.5, 1, 5, 10, 15 and 20 minutes (for dissolution samples 1 to 3) and at 1, 2, 3, 4, 5, 7 and 10 minutes (for dissolution samples 4 to 6) dry film for sampling.

The fast-dissolving form is a solid dispersion of the drug into a porous matrix. After administration, the dosage form disintegrates rapidly in the oral cavity and allows fast-dissolving drug to be absorbed by direct diffusion into the systemic circulation and avoids the first-pass effect. The present invention has the potential to provide an alternative route of drug administration and results in a lower rate of side effects.

Example 2

Formulations of the invention in the form of solid dosage forms (wafers) containing ketamine were prepared according to the method and ingredients as set forth below in Table 3:

Table 3: Composition of instant solid dosage forms of ketamine (strength equivalent is 25 mg ketamine base)

Composition (BP/USP) amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15

polyethylene glycol 2000 5 0.36 Glycine 1 0.07 microcrystalline cellulose 2 0.15 Amylopectin 50 3.64 Ketamine 62.5 4.55 lactose 100 7.28 Mannitol 150 10.92 purified water 1000 72.81

A dosage form wafer containing ketamine was produced using the method of Example 1 above.

The following other formulations were prepared by the method of Example 1. Samples 1 to 6 were based on the above formulation (strength equivalent is 25 mg ketamine base), with flavoring and/or coloring added.

Sample 1. Additionally contained flavoring.

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 polyethylene glycol 2000 5 0.35 orange flavoring 10 0.71 Glycine 10 0.71 microcrystalline cellulose 20 1.42 Amylopectin 50 3.54 Ketamine 62.5 4.43 lactose 100 7.09 Mannitol 150 10.63 purified water 1000 70.90

Sample 2. Additionally contained a flavoring agent and a pH adjuster (citric acid).

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 citric acid 5 0.35 polyethylene glycol 2000 5 0.35 mint flavoring 10 0.71 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.50 4.42

lactose 100 7.06 Mannitol 150 11.09 purified water 1000 70.65

Sample 3. Additional flavoring and coloring agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 polyethylene glycol 2000 5 0.35 grape flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.42 Amylopectin 50 3.54 Ketamine 62.5 4.43 lactose 100 7.09 Mannitol 150 10.43 purified water 1000 70.90

Sample 4. Additional flavoring, coloring and absorption enhancers

Element amount (g) weight% FD&C blue 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 β-cyclodextrin 5 0.35 polyethylene glycol 2000 5 0.35 grape flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.5 4.42 lactose 100 7.06 Mannitol 145 10.24 purified water 1000 70.65

Sample 5. Additionally contains coloring and sweetening agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07

Sodium carboxymethyl cellulose 2 0.14 aspartame 5 0.35 polyethylene glycol 2000 5 0.35 cherry flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.5 4.42 lactose 100 7.06 Mannitol 145 10.24 purified water 1000 70.65

Sample 6. Contains colorants and pH regulators additionally

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 sodium bicarbonate 5 0.35 polyethylene glycol 2000 5 0.35 raspberry flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Ketamine 62.5 4.42 lactose 100 7.06 Mannitol 145 10.24 purified water 1000 70.65

Ketamine instant solid dosage forms (wafers) of various strengths were then prepared based on the formulation shown in Table 3 and prepared as described in Example 1 above. Batch numbers and ingredients are listed in Table 4.

Table 4: Ketamine Compositions for Study

· In vitro studies

The in vitro study was aimed at characterizing the physicochemical properties of a freeze-dried instant solid dosage form of ketamine (equivalent to 25 mg ketamine base).

Weight Uniformity

Ketamine wafers were tested for weight uniformity as provided in Example 1. Twenty wafers from the formulations listed in Table 4 were individually weighed and the average weight and relative standard deviation calculated. All prepared wafers from different formulations were within the accepted weight variation of 0.25 to 2%.

hardness

The hardness of the wafers was also tested according to the method given in Example 1. The hardness values for the different formulations ranged from 0.5 to 4.0 kg. Batch 20110528 gave a hardness of 0.5 to 1.0 kg, and this formulation was then used in subsequent clinical trials. This formulation enables a fast dissolution rate and allows for easy handling.

Friability

The strength of the ketamine wafer was tested according to the method of Example 1. A sample of 20 ketamine wafers had a percent weight loss between 8 and 20%.

Moisture analysis

Ketamine wafers were analyzed for moisture content as provided in Example 1. The results showed that the residual moisture content was about 4%.

Scanning Electron Microscopy

The surface morphology and cross-sections of selected wafer formulation samples were observed using the method provided in Example 1. The SEM images shown in Figures 36 and 37 illustrate the highly porous nature of both the surface and internal structure of the ketamine-containing wafer.

Powder X-ray Diffraction (XRD)

The powder X-ray diffraction experiment was carried out using the method of Example 1.

The physical state of the material in the ketamine-containing wafer was evident in the X-ray diffraction spectrum. The spectra of three different formulations prepared according to Table 4 are shown in Figures 38, 39 and 40. All powder patterns of the prepared wafers were observed to be dominated by strong scattering peaks at approximately 2Θ of 9.58°, 19, 68° and 20.05°, indicating that the excipient Avicel has a crystalline nature. This finding is also supported by data generated from SEM. In fact, the excipients used in the formulation (such as glycine, lactose, mannitol and microcrystalline cellulose) are crystalline in nature. However, after freeze drying, all became amorphous.

Disintegration and Dissolution Analysis

Disintegration and dissolution tests were performed according to Example 1.

For the disintegration test, it was shown that the ketamine-containing wafer of the present invention was able to completely dissolve in about 15 seconds without leaving any residue.

For dissolution testing, ketamine-containing wafers from lot 20110528 were used to determine the level of drug released from the formulation. The dissolution rate of ketamine wafers was determined in a large volume (200 mL of phosphate buffered saline, 25 mM, pH 6.8) at a basket rotation speed of 75 rpm. At given intervals (eg, 1, 3, 5, 7, 10, 15, 20, and 30 minutes), 1.0 mL of the solution was sampled and replaced with an equal volume of fresh medium. Release was measured by HPLC with a C18 column (150 x 4.6 mm, 5 μm), mobile phase of 15% v/v acetonitrile in 85% 50 mM H ₃ PO ₄ , 20 mM triethylamine hydrochloride (pH 3.00) at ambient temperature drug, and the flow rate is 1.5ml/min. The monitoring wavelength is at 210nm. The HPLC chromatograms of dissolved ketamine wafers are shown in Figures 41-48.

The calibration curve (seven-point calibration) for concentrations from 5 to 100 μg/mL was linear [Y=16225X+3328.9, (R2=1), Y represents the peak area of ketamine, and X represents the concentration of the sample]. The assay standard curve is shown in Figure 49.

The prepared ketamine wafer (Lot 20110528) showed a weight change of ± 2.55% and the average percentage ketamine content of the wafer was 98.67% (BP standard 85 to 115% for uniformity content limit). The HPLC chromatogram is shown in Figure 50.

The mean disintegration time (BP disintegration device) was less than 5 seconds; and dissolution studies also indicated that ketamine had a rapid release rate. Almost 95% of the ketamine had dissolved within 1 minute. This may indicate a change in the crystalline form of ketamine in the wafer, which is also evident in X-rays. X-ray spectroscopy indicated that amorphization of ketamine occurred during the freeze-drying process.

The dissolution profile is presented in Figure 51.

Ketamine wafers are solid dispersions of ketamine hydrochloride into a porous matrix. After administration, the dosage form disintegrates rapidly in the oral cavity and allows absorption of the instant ketamine by direct diffusion into the systemic circulation and avoids the first-pass effect. The present invention has the potential to provide an alternative route of drug administration and results in a lower rate of side effects.

·In vivo studies

The objectives of the in vivo study were: 1) to study the pharmacokinetic profile of ketamine wafers (equivalent to 25 mg ketamine base, lot number: 20110528 in Table 4); 2) to determine the absolute biological activity of a single 25 mg sublingual dose of ketamine wafers. Utilization; and 3) Evaluation of clinical characteristics and acceptability of the invention using modified Likert and Bond and Lader scales.

Ethical Approval

The protocol was approved by the Royal Adelaide Human Research Ethics Committee (Royal Adelaide Human Research Ethics Committee). The trial is registered with the Australian Therapeutic Goods Administration (CTN: 2011/0292) in accordance with the clinical trial notification process.

research subjects

All volunteers gave their written informed consent on an approved subject consent form prior to being subjected to the trial procedure. Subjects included in the study were between 19 and 41 years of age, had a body mass index between ²² and 30 kg/m2, did not have a history of or exhibited drug or alcohol dependence or abuse, Normal findings on clinical history and laboratory tests, no sublingual or cheek sores or disease, and negative findings on HIV, Hepatitis B, and Hepatitis C virus testing.

A total of 8 healthy men who met the study inclusion and exclusion criteria were recruited into this study.

Research Planning and Design

This was a single-centre (Royal Adelaide Hospital Pain and Anesthesia Research Clinic, Adelaide, SA 5005, Australia), randomized, open-label, single-dose, dual-treatment, two-period, two-way crossover study. According to the randomization plan, subjects were divided into two groups in a 1:1 ratio using a computer-generated random number table.

Volunteers received both a single 10 mg intravenous (IV) dose of ketamine (diluted to 30 mL in saline and administered as an IV infusion over 30 minutes) and a 25 mg sublingual (SL) wafer dose of ketamine. The order of treatment sessions was balanced and randomized. It is applied by placing a wafer under the tongue. Volunteers were asked to refrain from swallowing for at least 10 minutes to minimize loss of ketamine via the oral route and thus via intestinal and hepatic metabolism (first pass effect). The total study duration was 4 weeks, including a 14-day screening period and a 7-day washout period.

Pharmacokinetics, tolerability and safety were measured for 24 hours following both dosing occasions. The total hospital stay at the Pain and Anesthesia Research Clinic was 28 hours (in Session 1) and 29 hours (in Session 2).

Before dosing (within 5 minutes of the scheduled dosing time), at 5, 10, 15, 30, 35, and 45 minutes after dosing, and at 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 Blood samples (5 mL) were obtained to quantify ketamine concentrations after both IV and SL administrations and 24 hours. Samples up to and including the 8-hour post-dose sample will be collected within 2 minutes of the nominal time, after which all post-dose samples will be collected within 10 minutes of the nominal time. Actual blood collection times are recorded in the source file. All deviations outside the window specified above will be recorded as protocol deviations. The total amount of blood to be obtained throughout the duration of the study was approximately 275 mL.

Immediately after collection, blood samples were centrifuged at 2000-2500g for 15 minutes at 4°C, and plasma was extracted and placed into polypropylene storage tubes. Plasma was stored at -80°C ± 10°C until transferred to a bioanalytical laboratory.

Pharmacokinetic Analysis

Plasma concentrations of racemic ketamine were analyzed with UV detection using a validated HPLC method with a lower limit of quantitation of 2 ng/mL and a bias and imprecision of <20%.

Standard non-compartmental analysis was used to obtain pharmacokinetic variables other _{than Cmax , tmax} , and _tfirst , _which were _observed as plasma concentration-time profiles for each subject The result is fetched. Actual times are used when reporting _tmax . Terminal rate constants (λ _z ), ie, the slope of the natural log concentration versus time curve, were estimated by log-linear regression, where λ _z =-1*slope. Linear regression in the terminal period used the last 3 to 6 data points, with a minimum of 3 points. The terminal t _1/2 is calculated as t _1/2 =ln(2)/λ _z .

The area under the plasma concentration time curve up to the last quantifiable plasma concentration (AUC _last ) was obtained using the linear up and log down method and extrapolated by C _last /λ _z (last quantifiable plasma concentration divided by λ _z ) to infinity to get the total AUC AUC _INF . The extrapolated part of AUC ( _AUCextr ) is obtained by (1- _AUCtlast / _AUCINF )*100. The total area under the first moment curve, AUMC _INF , was calculated in a similar manner to AUC _INF and MRT to obtain the AUMC _INF /AUC _INF corrected mean residence time (MRT _iv ) for the duration of the 30-minute IV infusion. Clearance (CL) for IV administration was calculated as dose/AUC _INF and was calculated in the same manner for sublingual administration. Clearance by non-IV routes is expressed as CL/F, the ratio of clearance to bioavailability, since the latter is unknown. The volume of distribution V _z is calculated as CL/λ _z . The MAT for sublingual administration was obtained as the difference between the MRTs of the two routes of administration (as MRT _SL −MRT _IV ). The bioavailability (F) of ketamine was calculated as the ratio of dose-adjusted AUC _INF following IV and sublingual administration according to _AUCSL / _AUCIV *Dose _IV / _DoseSL .

Safety and Tolerability

Safety assessments included scheduled adverse event (AE) detection, spontaneous AE reports, routine laboratory studies, 12-lead electrocardiogram (ECG) and vital sign assessment during the 24-hour period from start of dosing. A full physical examination was performed prior to the first dosing occasion and 24 hours after the second dosing occasion.

Local tolerance was assessed before dosing, 5, 10, 15, 30 and 45 minutes and 1 hour after dosing by using a Likert scale. Execute before dosing, 30 minutes after dosing and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 hours after dosing and "Calm" to assess sedation and the modified Bond and Reid scale for perceived changes.

Statistical Analysis

Standard summary statistics were calculated by processing each pharmacokinetic variable. 90% confidence intervals (CI) for bioavailability were calculated.

result

Individual values and summary statistics for volunteer characteristics are reported in Table 5.

Table 5: Subject Demographics

Plasma Concentrations of Racemic (RS) Ketamine

Overlapped geometric means (g- _mean ) of individual RS ketamine plasma concentrations for all subjects following IV administration for the entire sampling period are depicted in FIG. 52 . For clarity, the first 12 hours after dosing are shown separately in Figure 53. Overlapped geometric means of individual RS ketamine plasma concentrations for all subjects for the entire sampling period following SL administration are shown in Figure 54 and the first 12 hours in Figure 55.

The IV and SL plasma concentration time profiles were similar in shape, except for 4 subjects with 2-3 peaks for the SL route. After _Cmax , the concentration of both IV and SL decreased biphasically, but the trend was more prominent for IV.

All subjects had first quantifiable concentrations within 5 minutes after both IV and SL administration, indicating rapid absorption of SL administration. For SL dosing, 6 subjects had plasma concentrations below the limit of quantitation at 24 hours and 1 subject at 12 hours. Following IV dosing, all subjects had quantifiable levels at 12 hours and 4 subjects had quantifiable levels at 24 hours.

After IV dosing, C _max occurred at the end of the infusion in all subjects except one subject (No. _Cmax was observed in samples taken 5 minutes after end of injection.

For SL dosing, the median time to the main peak (ie, t _max ) was 0.75 hours, with the earliest peak detected at 0.25 hours after dosing and the latest peak detected at 1 hour after dosing. Subjects 4, 5, 6 and 7 had multiple minor peaks in their plasma concentration time profiles observed during the first 3 hours after dose administration. Individual t _max values are shown in Figure 56.

Table 6 presents individual estimates and summary statistics for the main pharmacokinetic variables. Individual AUC _INF values for both routes of administration are shown in Figure 57. The extrapolated portion of AUC (AUC _extr ) for both routes of administration was extremely small, indicating high quality in estimating AUC values. For IV, AUC _extr was 3-7%, and for SL it was 2-9%.

Individual estimates of CL by the IV route are presented in Figure 58. After SL administration, CL was confounded by F and therefore cannot be compared with values obtained after IV administration. The median CL for IV administration was 37.7 L/h.

Terminal half-lives were similar after IV and SL administration, with median values of 4.5 and 3.4 hours, respectively. The similar half-lives of the IV and SL routes indicate that absorption is rapid, otherwise the slower absorption half-life would dominate the terminal phase of the plasma concentration time curve, and thus show a significantly longer half-life than IV administration. Individual values for the two routes of administration are provided in Figure 59.

Bioavailability and Absorption

SL wafers dissolved within 30 seconds to 1 minute in most subjects.

Individual estimates of bioavailability are shown in Figure 60, and individual bioavailability and MAT (mean absorption time) values are provided in Table 7 along with summary statistics. Subject No. 8 had a bioavailability significantly higher than the other subjects by 38%. Apart from having the highest extrapolated areas 9% (for SL) and 7% (for IV) and bimodal (for SL dosing), this subject was not significantly different from the other subjects. The median and 90% CI [lower, higher] of bioavailability was 29 [27,31]%, thus showing very low inter-subject variability.

Table 7: Individual (subject = randomization number), median, minimum and maximum RS ketamine bioavailability (F) and mean absorption time (MAT) following SL administration of 25 mg to 8 healthy volunteers.

*not applicable

MAT represents the average time it takes for a ketamine molecule to travel from the site of administration (ie, the SL space) to the systemic circulation. Individual MRT values for both routes of administration were similar, with median values of 3.9 hours (for IV) and 3.8 hours (for SL), indicating rapid absorption. A small difference between the MRT of IV and SL (ie small MAT) indicates rapid absorption. Due to naturally occurring variability, negative values may result when taking the difference between two similar values, as seen in some MAT values.

In conclusion, the PK of SL wafers is characterized by rapid absorption and low variability in bioavailability. This, along with lower variability in clearance, translates into lower variability in exposure. The low variability allows for increased accuracy in predicting the total exposure and thus pharmacological effects of SL wafers, which may be expected to increase its utility in the clinical setting.

Pharmacodynamic results

Bond and Reid Emotion Rating Scale

The Bond and Reid scale consists of a total of 16 100mm lines anchored by antonyms at either end. Participants marked their current subjective state between antonyms on the line. Each line is scored in millimeters from the negative antonym to the mark. Based on the resulting scores, three measures obtained through factor analysis were identified. These measures have been described by Bond and Reid as representing the following elements:

Element 1: "Vigilance" (consisting of being vigilant-hypnotized, concentrating-trance, dull-vigorous, dazed-clear, well-coordinated-clumsy, mentally retarded-intelligent, strong-weak, interested-bored, not Competent – proficient in anchored line representations);

·Element 2: "peace of mind" (peace of mind - restlessness, trouble - tranquility, happiness - sadness, hostility - friendliness, introversion - love to communicate) and

• Element 3: "Calm" (calm-excited, tense-relaxed); the score for each element represents the unweighted mean millimeters (maximum 100 mm) of the individual scale that facilitates the negative antonym of said element.

Thus, the maximum score for element 1 is 900; element 2 is 500, and element 3 is 200.

Mood rating scales showed ambiguous trends in achievement effects. After SL administration, the elements "vigilance" and "peace of mind" fluctuated around pre-dose levels during the entire 24-hour observation period, while "calm" showed that during the first hour after dosing may be due to Local tolerability observations during -60 minutes present an initial decrease in excitation, followed by a steady increase and complete recovery by 2.5 hours post-dose. The shape of the curve after IV dosing was similar to that of SL dosing. The plots of mean (SD) values for each element of the Mood Rating Scale following IV and SL dosing are depicted in Figure 61 and Figure 62, respectively.

Modified Likert Local Tolerance Scale

A modified Likert scale was used to assess the following symptoms: cheek irritation; burning sensation; bitter taste and nausea. As expected, all values were generally zero after IV administration, but there were sporadic values of 1 or 2. Following SL application, values for "cheek irritation" were generally zero or sporadically 1 or 2, and values for "burning sensation" were similar, but there was a single value of 3 reported by subject 3 at 10 min. For 'nausea' the values showed the same trend as for the IV, with mostly zero values but with sporadic values of 1 or 2. However, the values for "bitterness" differed from the IV; all subjects reported non-zero values after dosing, but peaks in the range 1-9, with 1 subject reporting peaks 1 and 3 each, and the rest of the subjects or greater than 5. The highest value was at 5 minutes in 4 subjects; at 10 minutes in 2 subjects; at 15 minutes in 1 subject, and at 5 minutes in 1 subject and 10 minutes both reported a value of 9. All values had returned to zero by 1 hour (Figure 63).

There were no clinically relevant abnormal changes or trends in ECG, vital signs, hematology, clinical chemistry, or urinalysis.

In conclusion, sublingual wafer formulations of ketamine have been developed as a potential adjunct in acute and chronic pain management and other conditions. The median bioavailability for this example was 29%, with very low inter-subject variability, which favors relatively narrow therapeutic index drugs such as ketamine. Low variability also increases the utility of the wafer in terms of reproducible exposure and thus analgesic effect. Except for mild and transient CNS-type symptoms, administration of ketamine in the form of 25 mg sublingual wafers to healthy volunteers was safe and well tolerated, as expected based on existing clinical experience with ketamine. Local tolerability was excellent and any local irritation was expected to be mild and dissipate within 30-60 minutes after dosing.

Example 3

Formulations of the invention in the form of solid dosage forms (wafers) containing sildenafil were prepared according to the method and ingredients as set forth below in Table 8:

Table 8: Composition of sildenafil instant solid dosage form (strength equivalent is 25 mg sildenafil base).

Element amount (g) weight% Sodium Carbonate BP/USP 1 0.07 Sodium Carboxymethyl Cellulose BP/USP 2 0.14 Polyethylene glycol 2000BP/USP 5 0.34 Glycine BP/USP 10 0.68 Microcrystalline Cellulose BP/USP 10 0.68 Citric acid BP/USP 10 0.68 Pullulan BP/USP 50 3.42 LactoseBP/USP 100 6.84 Mannitol BP/USP 150 10.25 Sildenafil BP/USP 125 8.54 Purified water BP/USP 1000 68.35

A dosage form wafer containing sildenafil (25 mg) was produced using the method of Example 1 above.

The following other formulations were prepared by the methods set forth above. Samples 1 to 6 were basically based on the above formulations with the addition of flavoring and/or coloring agents.

Sample 1. Additionally contained flavoring.

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 polyethylene glycol 2000 5 0.37 orange flavoring 10 0.74 Glycine 10 0.74 citric acid 10 0.74 microcrystalline cellulose 20 1.47 Amylopectin 50 3.68 lactose 100 6.84 Mannitol 150 10.25

Sildenafil BP/USP 125 8.54 purified water 1000 66.41

Sample 2. Additional flavoring and pH adjuster (citric acid)

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 polyethylene glycol 2000 5 0.37 citric acid 10 0.74 mint flavoring 10 0.74 Glycine 10 0.74 microcrystalline cellulose 20 1.47 Amylopectin 50 3.68 lactose 100 6.84 Mannitol 150 10.25 Sildenafil BP/USP 125 8.54 purified water 1000 67.15

Sample 3. Additional flavoring and coloring agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 polyethylene glycol 2000 5 0.37 grape flavoring 9.9 0.73 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 6.84 Mannitol 150 10.25 Sildenafil BP/USP 125 8.54 purified water 1000 67.11

Sample 4. Additional flavoring, coloring and absorption enhancers

Element amount (g) weight% FD&C blue 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 β-cyclodextrin 5 0.37

polyethylene glycol 2000 5 0.37 grape flavoring 9.9 0.73 Glycine 10 0.74 citric acid 10 0.74 microcrystalline cellulose 20 1.47 Amylopectin 50 3.71 lactose 100 6.84 Mannitol 150 10.25 Sildenafil BP/USP 125 8.54 purified water 1000 66.01

Sample 5. Additionally contains coloring and sweetening agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 aspartame 5 0.37 polyethylene glycol 2000 5 0.37 cherry flavoring 9.9 0.73 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 6.84 Mannitol 150 10.25 Sildenafil BP/USP 125 8.54 purified water 1000 66.74

Sample 6. Additionally contains colorants and pH regulators

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 sodium bicarbonate 5 0.37 polyethylene glycol 2000 5 0.37 raspberry flavoring 9.9 0.73 Glycine 10 0.74 microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 lactose 100 6.84 Mannitol 150 10.25 Sildenafil BP/USP 125 8.54

purified water 1000 66.74

Various batches of sildenafil instant solid dosage wafers were then prepared based on the formulation shown in Table 8 and prepared as described in Example 1 above. Batch numbers and ingredients are listed in Table 9.

Table 9: Composition of the sildenafil formulations studied (strength equivalent is 25 mg sildenafil base)

· In vitro studies

Weight Uniformity

The weight uniformity of the sildenafil wafers was tested as provided in Example 1. Twenty wafers from the formulations listed in Table 9 were individually weighed and the average weight and relative standard deviation calculated. All prepared wafers from different formulations were within the accepted weight variation of 0.25 to 2%.

hardness

The hardness of the wafers was also tested according to the method given in Example 1. The hardness values for the different formulations ranged from 0.5 to 4.0 kg. Batch 20120628 yielded wafers with a hardness of 0.5 to 1.0 kg, and this formulation was used in subsequent clinical trials. This formulation enables a fast dissolution rate and allows for easy handling.

Friability

The strength of sildenafil wafers (including their ability to reduce from solid matter into smaller fragments) was measured according to the method given in Example 1. A sample of 20 sildenafil wafers had a percent weight loss between 8 and 20%.

Moisture analysis

The moisture content of the sildenafil wafers was analyzed as provided in Example 1. The results showed that the residual moisture content was about 4%.

Scanning Electron Microscopy

The surface morphology and cross-sections of selected wafer formulation samples were observed using the method provided in Example 1. The SEM images shown in Figures 64 and 65 show clear morphological differences between blank and sildenafil wafers.

Powder X-ray Diffraction (XRD)

The powder X-ray diffraction experiment was carried out using the method of Example 1.

The physical state of the substances in the sildenafil wafers is evident in the X-ray diffraction spectrum. The spectra of three different formulations as prepared according to Table 9 are shown in Figures 66, 67 and 68. All powder patterns of the prepared wafers were observed to be dominated by strong scattering peaks at approximately 2Θ of 9.58°, 19, 68° and 20.05°, indicating that the excipient Avicel has a crystalline nature. This finding is also supported by data generated from SEM. In fact, the excipients used in the formulation (such as glycine, lactose, mannitol and microcrystalline cellulose) are crystalline in nature. However, after lyophilization, all appeared to become amorphous.

Disintegration and Dissolution Analysis

Disintegration and dissolution tests were performed according to Example 1.

For the disintegration test, it was shown that the sildenafil-containing wafer of the present invention is able to dissolve completely within about 15 seconds without leaving any residue.

For dissolution testing:

Dissolution testing was performed using Apparatus I (BP 2009, rotating basket apparatus). An Erweka dissolution apparatus (Hesenstamm, Germany) was used for both experiments. The temperature of the medium was maintained at 37±0.5°C. Wafers containing sildenafil (batch 20120628) were used to determine the level of drug released from the formulation. The dissolution rate of the sildenafil wafers was determined using the method given in Example 2.

The calibration curve (seven-point calibration) for sildenafil at concentrations from 5 to 100 μg/mL was linear [Y=32.973X-36538, (r=0.9999), Y represents the peak area of sildenafil, and X represents the concentration of the sample]. The assay standard curve is shown in Figure 77.

The prepared sildenafil wafers (batch 20120628) showed a weight variation of ±2.55% and the average sildenafil content percentage of the wafers was 98.67% (BP standard 85 to 115% for uniformity content limits). The mean disintegration time (BP disintegration device) was less than 5 seconds; and dissolution studies also indicated that sildenafil had a fast release rate. Almost 95% of the sildenafil was dissolved within 1 minute. This may indicate a change in the crystalline form of sildenafil in the wafer, which is also evident in X-rays. X-ray spectroscopy indicated that sildenafil was amorphized during the freeze drying process.

The dissolution profile is presented in Figure 78.

Sildenaphne wafer is a solid dispersion of sildenafil hydrochloride into a porous matrix. After administration, the dosage form disintegrates rapidly in the oral cavity and allows the instant sildenafil to be absorbed by direct diffusion into the systemic circulation and avoids the first-pass effect. The present invention has the potential to provide an alternative route of drug administration and results in a lower rate of side effects.

Example 4

Formulations of the invention in the form of epinephrine-containing solid dosage forms (wafers) were prepared according to the method and ingredients as set forth below in Table 10:

Table 10: Composition of epinephrine instant solid dosage form (strength equivalent is 40 mg epinephrine base)

Composition (BP/USP) amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.15 polyethylene glycol 2000 5 0.36 Glycine 1 0.07 microcrystalline cellulose 2 0.15 Amylopectin 50 3.64 Adrenaline (base) 100 7.28 lactose 100 7.28 Mannitol 150 10.92 purified water 1000 70.08

A fast dissolving form (wafer) containing epinephrine was produced using the method of Example 1 above.

The following other formulations were prepared by the methods set forth above. Samples 1 to 6 are based on the above formulation (strength equivalent is 40 mg epinephrine base) with the addition of flavoring and/or coloring agents.

Sample 1. additionally contains flavoring

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 polyethylene glycol 2000 5 0.35 orange flavoring 10 0.71 Glycine 10 0.71 microcrystalline cellulose 20 1.42 Amylopectin 50 3.54 Adrenaline (base) 100 7.09 lactose 100 7.09 Mannitol 150 10.63 purified water 1000 68.25

Sample 2. Additionally contained a flavoring agent and a pH adjuster (citric acid).

Element amount (g) weight% Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 citric acid 5 0.35 polyethylene glycol 2000 5 0.35 mint flavoring 10 0.71 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Adrenaline (base) 100 7.06 lactose 100 7.06 Mannitol 150 11.09 purified water 1000 67.52

Sample 3. Additional flavoring and coloring agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 polyethylene glycol 2000 5 0.35 grape flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.42 Amylopectin 50 3.54 Adrenaline (base) 100 7.09 lactose 100 7.09 Mannitol 150 10.43 purified water 1000 68.45

Sample 4. Additional flavoring, coloring and absorption enhancers

Element amount (g) weight% FD&C blue 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 Glyceryl trinitrate 28.57 2.00 polyethylene glycol 2000 5 0.35 grape flavoring 9.9 0.70 Glycine 10 0.71

microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Adrenaline (base) 100 7.06 lactose 100 7.06 Mannitol 145 10.24 purified water 1000 66.72

Sample 5. Additionally contains coloring and sweetening agents

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 aspartame 5 0.35 polyethylene glycol 2000 5 0.35 cherry flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Adrenaline (base) 100 7.06 lactose 100 7.06 Mannitol 145 10.24 purified water 1000 68.42

Sample 6. Additionally contains colorants and pH regulators

Element amount (g) weight% FD&C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethyl cellulose 2 0.14 sodium bicarbonate 5 0.35 polyethylene glycol 2000 5 0.35 raspberry flavoring 9.9 0.70 Glycine 10 0.71 microcrystalline cellulose 20 1.41 Amylopectin 50 3.53 Adrenaline (base) 100 7.06 lactose 100 7.06 Mannitol 145 10.24 purified water 1000 68.37

Epinephrine bitartrate instant solid dosage forms (wafers) of various strengths were then prepared based on the formulation shown in Table 10 and prepared as described in Example 1 above. Batch numbers and ingredients are listed in Table 11.

Table 11: Epinephrine Compositions for Study

Example 5

Phase I pharmacokinetics and biochemistry of sublingual fentanyl wafers in healthy volunteers Bioavailability Studies

·method

research subjects

Healthy volunteers gave written informed consent on approved subject consent forms prior to being subjected to experimental procedures. Subjects included in the study were between 19 and 32 years of age, had a body mass index between ¹⁸ and 30 kg/m2, had no history or signs of drug or alcohol dependence or abuse, after clinical history and laboratory tests Has normal findings, no SL (sublingual) or cheek sores or disease, and has negative findings on human immunodeficiency virus, hepatitis B, and hepatitis C virus testing.

Twenty-four volunteers who met the study inclusion and exclusion criteria were recruited into this study. Values of 35% and 20% significant difference were given a power of 84% based on the SD of the area under the curve (AUC) (α = 0.05).

Research design

This was a single center (Linear Clinical Research Ltd, Perth, Australia), randomized, open label, single dose, dual treatment, two phase, two way crossover study. According to the randomization plan, subjects were divided into 2 groups in a 1:1 ratio using a computer-generated random number table. Volunteers were administered IV fentanyl citrate or sublingual fentanyl citrate wafers (based on batch: 1003 FEN formulation of Example 1; equivalent to 100 μg fentanyl). Each volunteer then received an alternative route after a 7-day washout period.

It is applied by placing a wafer under the tongue. Volunteers were asked to refrain from swallowing for as long as possible (for at least 10 minutes). Orally administer naltrexone tablets (50 mg) every 12 hours from before Day 1 until the evening of Day 2 (12 hours after the last fentanyl dose) to block any systemic effects of fentanyl effect.

Prior to the start of the study, a dedicated IV catheter was placed in the forearm for subsequent venous blood sampling. Acquired pre-dose prior to initiation of wafer administration, followed by 2, 5, 10, 15, 20, 30, 45, 60, 120, 180, 360, 460, 600, 720, 960, and 1440 minutes after initiation of administration Blood samples (7 mL). For IV infusions, before dosing, at 2 and 3 minutes after start, and at 5 minutes (end of infusion), followed by 7, 10, 15, 20, 25, 30, 45, 60, Blood samples were taken at 120, 180, 360, 460, 600, 720, 840, 960 and 1440 minutes.

Immediately after collection, blood samples were centrifuged at 2000 to 2500 g for 15 minutes at 4°C, and plasma was extracted and placed into polypropylene storage tubes. Plasma was stored at -80°C ± 10°C until transferred to a bioanalytical laboratory. Sample extracts were analyzed on an API 4000LC-MS/MS system (Applied Biosystems, Foster City, CA) preceded by a Shimadzu Prominence high-performance liquid chromatography system with d5-fentanyl as an internal standard. The assay had a detection limit of 10 pg/mL. Precision was determined by analyzing plasma containing 10, 40 and 400 pg/mL fentanyl in duplicate. The results were accurate within ±6.2%, ±3.3% and ±1.7% for the mean measured concentration values of 10, 40 and 400 pg/mL, respectively, and within 102%, 99.9% for the nominal concentrations of 10, 40 and 400 pg/mL, respectively. % and within 101.4% to be exact. The number of replicates was 6 at each concentration.

Pharmacokinetic Analysis

Pharmacokinetic parameters were determined using Phoenix WinNonlin version 6.1 (Pharsight, A Certara ^™ Company, St. Louis, MO). Pharmacokinetic data are C _max , t _max , AUC _0-12 , AUC _0-t , AUC _0-∞ , _kel and t _1/2 . The first detectable plasma concentration of fentanyl (C _first ) and the time to reach C _first (t _first ) after SL administration were read directly from the plasma fentanyl concentration-time curve. The terminal elimination rate constant ( _kel ) was determined as the slope of the regression line that best fits the approximately log-linear terminal elimination phase. All fits are performed with uniform weighting of the data. The terminal elimination half-life (t _1/2 ) was obtained from k _el and was equal to ln 2 /k _el . AUC _0-12 and AUC _0-t values were obtained using the trapezoidal rule. Extrapolation to AUC _0-∞ calculated from AUC _0-t + C _t / _kel .

Safety and Tolerability

Safety and tolerability were assessed by monitoring vital signs (arterial blood pressure and heart rate) after fentanyl administration. A full physical examination was performed prior to drug administration and 48 hours after drug administration. Laboratory tests and 12-lead electrocardiograms were performed at baseline and at study completion. Adverse events were assessed using direct observation, spontaneous reporting, and nonspecific questioning.

Statistical Analysis

Summary statistics were calculated by processing each pharmacokinetic parameter. The bioavailability of SL fentanyl was determined for each subject as the ratio of Cmax, AUC _0-12 , AUC _0-t and AUC _0-∞ administered SL compared to IV administered, respectively. Overall bioavailability was estimated as log-transformed C _max , AUC _0-12 , AUC _0-t and AUC _0-∞ values using a linear model for treatment, time period, sequence, and subject within sequence The inverse transform form of the difference between treatments. A 90% confidence interval (CI) was also calculated, and a P value <0.05 was considered statistically significant. All analyzes were performed using SAS version 9.2 (SAS Institute Inc., 2008). Formulation differences were assessed using the Student's t test.

·result

24 patients were randomized, 12 entered the SL:IV sequence, and 12 entered the IV:SL sequence. Two volunteers did not complete the study in the SL or IV administration groups and were removed from all analyses. Volunteer characteristics are reported in Figure 79.

Pharmacokinetic Results

The mean plasma (±SEM) fentanyl concentration versus time profiles for the IV and SL routes are shown in FIG. 80 . Individual subject plasma concentration profiles for the SL route are shown in Figure 81. The mean values (±1 SD) of the plasma pharmacokinetic parameters C _max , t _max , AUC _0-12 , AUC _0-t and AUC _0-∞ of fentanyl are shown in FIG. 82 . The first detectable plasma fentanyl concentration after SL administration (C _first ) was observed between 2 and 10 minutes after administration. The cumulative percentages of the 22 volunteers at t _first at 2, 5 and 10 minutes and their mean plasma fentanyl concentrations (C _first ) were 12.5% (32.4pg/mL), 62.5% (30.7pg/mL) and 100.0% (49.0 pg/mL).

The mean time to peak plasma concentration (t _max ) after initiation of IV and SL administration was 0.12 hours and 0.92 hours (P<0.0001 ), respectively (Figure 82). The mean (±SD) terminal half-life (t _1/2 ) was 13.07±3.00 hours and 12.49±5.24 hours for IV and SL administration, respectively (P=0.889). The mean (±SD) terminal elimination rate constant ( _kel ) was 0.055±0.012 h ⁻¹ and 0.064±0.025 h ⁻¹ for IV and SL administration, respectively (P=0.317).

Bioavailability was assessed by the percentage SL/IV ratio of AUC _0-12 , AUC _0-t and AUC _0-∞ values. The mean bioavailability of SL fentanyl estimated from AUC _0-12 was 72.1% (CI 65.3% to 79.6%), and the mean bioavailability of SL fentanyl estimated from AUC _0-t was 73.2% ( CI 66.3% to 80.9%). The absolute bioavailability based on the AUC _0-∞ value was 78.9% (CI 51.1% to 121.7%).

The _Cmax for SL fentanyl was 18.8% (CI 14.4% to 24.6%) of the value administered IV, with a mean time to reach maximum concentration of 0.9 hours. For IV administration, _Cmax typically occurs at the end of the infusion with a rapid decrease over the immediate half hour after dosing. Starting approximately 2 hours after dosing, the mean concentration-time profiles were similar for the 2 modes of administration.

tolerance

All reported adverse events were mild to moderate. The mean (±SD) time for the wafer to dissolve in the SL capsule was 73±76 seconds.

This study was designed as a phase I study to determine the basic pharmacokinetic parameters of a newly developed fast-dissolving fentanyl wafer. It also collects some data on the subject's acceptance of the product.

_Cmax and _tmax values for SL Fentanyl (100 μg) wafers were found to be similar ( FIG. 83 ) to data reported for SL Fentanyl (100 μg) tablets from a previous study. C _max and t _max values provide an indication of the rate of absorption of the drug. Wafers had similar C _max , t _max and AUC values compared to SL tablets (P = 0.573, 0.331 and 0.103, respectively); absolute bioavailability data for SL tablets were not available. Note that SL tablets were evaluated in cancer patients over a 10 hour collection period, which resulted in different t _1/2 values of 6.1 and 12.5 hours for the tablets and wafers, respectively (P=0.0013).

Fentanyl was rapidly absorbed as evidenced by plasma concentrations that were detectable within 2 to 10 minutes (t _first ) and in most cases within 5 minutes following SL administration. _Wafer formulations have a C _first similar to that of SL tablets. This reflects that fentanyl is highly permeable into the rich blood stream (and good venous outflow) of the SL mucosa, which bypasses the hepatic "first pass" effect. The SL mucosa (100 to 200 μm) is thicker than the nasal mucosa (40 to 80 μm); therefore the rate of absorption is expected to be slower compared to that reported after IN administration (in this study, the _tmax for IN fentanyl was 4.2 to 11.4 minutes compared to 54.6 minutes for SL fentanyl).

The high bioavailability of fentanyl from wafers suggests that wafer fentanyl is indeed absorbed sublingually and is less likely to be partially swallowed, thus avoiding first-pass metabolism. No attempt was made to assign bioavailability to these absorption routes in this study. Based on earlier pilot studies in postoperative patients, the analgesic efficacy of wafer formulations appears to be satisfactory.

The SL fentanyl wafer produced rapidly detectable plasma fentanyl concentrations in healthy volunteers within 10 minutes of administration, indicating potential for the treatment of breakthrough pain. Bioavailability relative to IV administration was 78.9%.

Claims (26)

1. be suitable for a solid dosage forms for release of bioactive substances in the oral cavity, wherein said dosage form comprises:

A) at least one bioactive substance, and

B) at least one matrix formers,

Wherein said dosage form is dissolved in the oral cavity substantially, and wherein said bioactive substance is selected from and comprises following inventory: at least one ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor, in conjunction with the active substance of one or more adrenoreceptors and N-methyl-D-aspartate receptor antagonist.

2. solid dosage forms as claimed in claim 1, wherein said solid dosage forms is Fast-dissolving solid forms.

3. solid dosage forms as claimed in claim 1, wherein said N-methyl-D-aspartate receptor antagonist is selected from and comprises following inventory: dextromethorphan, dextrorphan or ketamine.

4. solid dosage forms as claimed in claim 1, the described active substance wherein in conjunction with one or more adrenoreceptors is epinephrine (adrenal hormone) or epinephrine salt.

5. solid dosage forms as claimed in claim 1, described ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.

6., in order to produce the method being suitable for the solid dosage forms of release of bioactive substances in the oral cavity, wherein said dosage form is dissolved in the oral cavity substantially, said method comprising the steps of:

A) combination at least one matrix formers and bioactive substance are to form uniform homogeneous blend; And

B) mixture described in lyophilization is to prepare described solid dosage forms of the present invention

Wherein said bioactive substance is selected from and comprises following inventory: at least one ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor, in conjunction with the active substance of one or more adrenoreceptors and N-methyl-D-aspartate receptor antagonist.

7. method as claimed in claim 6, wherein said solid dosage forms is Fast-dissolving solid forms.

8. method as claimed in claim 6, wherein said N-methyl-D-aspartate receptor antagonist is selected from and comprises following inventory: dextromethorphan, dextrorphan or ketamine.

9. method as claimed in claim 6, the described active substance wherein in conjunction with one or more adrenoreceptors is epinephrine or epinephrine salt.

10. method as claimed in claim 6, wherein said ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.

11. 1 kinds of medicine boxs, it comprises:

A) be suitable for the solid dosage forms of release of bioactive substances in the oral cavity, wherein said dosage form is dissolved in the oral cavity substantially, and wherein said dosage form comprises:

(i) at least one bioactive substance, and

(ii) at least one matrix formers; And

B) operation instructions

Wherein said bioactive substance is selected from and comprises following inventory: at least one ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor, in conjunction with the active substance of one or more adrenoreceptors and N-methyl-D-aspartate receptor antagonist.

12. medicine boxs as claimed in claim 11, wherein said solid dosage forms is Fast-dissolving solid forms.

13. medicine boxs as claimed in claim 11, wherein said N-methyl-D-aspartate receptor antagonist is selected from and comprises following inventory: dextromethorphan, dextrorphan or ketamine.

14. medicine boxs as claimed in claim 11, the described active substance wherein in conjunction with one or more adrenoreceptors is epinephrine or epinephrine salt.

15. medicine boxs as claimed in claim 11, wherein said ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.

16. 1 kinds of solid dosage forms wafers being suitable for release of bioactive substances in the oral cavity, wherein said dosage form comprises:

A) at least one bioactive substance, and

B) at least one matrix formers,

Wherein said wafer dissolves in the oral cavity substantially, and wherein said bioactive substance is selected from and comprises following inventory: at least one ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor, in conjunction with the active substance of one or more adrenoreceptors and N-methyl-D-aspartate receptor antagonist.

17. wafers as claimed in claim 16, wherein said solid dosage forms is Fast-dissolving solid forms.

18. wafers as claimed in claim 16, wherein said N-methyl-D-aspartate receptor antagonist is selected from and comprises following inventory: dextromethorphan, dextrorphan or ketamine.

19. wafers as claimed in claim 16, the described active substance wherein in conjunction with one or more adrenoreceptors is epinephrine or epinephrine salt.

20. wafers as claimed in claim 16, wherein said ring-type Guanosine 5'-Monophosphate (cGMP) 5 type phosphodiesterase (PDE5) inhibitor is 'Xiduofeng ' or its pharmaceutically acceptable salt.

21. 1 kinds of pharmaceutical compositions, it comprises: as claim 1 or solid dosage forms according to claim 16.

22. solid dosage formss as claimed in claim 1, method as claimed in claim 6, medicine box as claimed in claim 11 or wafer as claimed in claim 16, wherein said dosage form is suitable for the residue that can be detected by patient not leaving described dosage form in the oral cavity.

23. solid dosage formss as claimed in claim 1, method as claimed in claim 6, medicine box as claimed in claim 11 or wafer as claimed in claim 16, wherein once place in the oral cavity, described dosage form namely be selected from by the time period of the following group formed substantially dissolve: after using described dosage form, be less than 2 minutes; Be less than 1 minute; Be less than 50 seconds; Be less than 40 seconds; Be less than 30 seconds; Be less than 20 seconds; Be less than 15 seconds; Be less than 10 seconds; Be less than 7.5 seconds; Be less than 5 seconds; Be less than 4 seconds; Be less than 3 seconds; And be less than 2 seconds.

24. solid dosage formss as claimed in claim 1, method as claimed in claim 6, medicine box as claimed in claim 11 or wafer as claimed in claim 16, wherein once place in the oral cavity, described dosage form namely be selected from by the time period of the following group formed completely dissolve: after using described dosage form, be less than 2 minutes; Be less than 1 minute; Be less than 50 seconds; Be less than 40 seconds; Be less than 30 seconds; Be less than 20 seconds; Be less than 15 seconds; Be less than 10 seconds; Be less than 7.5 seconds; Be less than 5 seconds; Be less than 4 seconds; Be less than 3 seconds; And be less than 2 seconds.

25. solid dosage formss as claimed in claim 1, method as claimed in claim 6, medicine box as claimed in claim 11 or wafer as claimed in claim 16, wherein said dosage form provides the effective plasma level concentration of described bioactive substance within the time period of 2 hours at the most, 30 minutes, 20 minutes or 15 minutes.

Thering is provided of 26. effective plasma level concentration as claimed in claim 25, the wherein said time period is in 10 minutes.